Selective β3 adrenergic agonists

ABSTRACT

The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to selective β3 adrenergic receptor agonists useful in the treatment of Type II diabetes and obesity. The invention provides compounds and method of treating type II diabetes, comprising administering to a mammal in need thereof compounds of the Formulas I and II: ##STR1##

This application is a division of application Ser. No. 08/708,621 filedSep. 5, 1996, abandoned.

FIELD OF THE INVENTION

The present invention is in the field of medicine, particularly in thetreatment of Type II diabetes and obesity. More specifically, thepresent invention relates to selective β₃ adrenergic receptor agonistsuseful in the treatment of Type II diabetes and obesity.

BACKGROUND OF THE INVENTION

The current preferred treatment for Type II, non-insulin dependentdiabetes as well as obesity is diet and exercise, with a view towardweight reduction and improved insulin sensitivity. Patient compliance,however, is usually poor. The problem is compounded by the fact thatthere are currently no approved medications that adequately treat eitherType II diabetes or obesity. The invention described herein is directedtoward an effective and timely treatment for these serious diseases.

One therapeutic opportunity that has recently been recognized involvesthe relationship between adrenergic receptor stimulation andanti-hyperglycemic effects. Compounds that act as β₃ receptor agonistshave been shown to exhibit a marked effect on lipolysis, thermogenesisand serum glucose levels in animal models of Type II (non-insulindependent) diabetes.

The β₃ receptor, which is found in several types of human tissueincluding human fat tissue, has roughly 50% homology to the β₁ and β₂receptor subtypes yet is considerably less abundant. The importance ofthe β₃ receptor is a relatively recent discovery since the amino-acidsequence of the human receptor was only elucidated in the late 1980's. Alarge number of publications have appeared in recent years reportingsuccess in discovery of agents that stimulate the β₃ receptor. Despitethese recent developments, there remains a need to develop a selectiveβ₃ receptor agonist which has minimal agonist activity against the β₁and β₂ receptors. In addition, indolylpropanolamines have been disclosedby Beedle et. al. U.S. Pat. 5,013,761.

The present invention provides compounds which are selective β₃ receptoragonists. As such, the compounds effectively lead to an increase ininsulin sensitivity and are useful in treating Type II diabetes andother ailments implicated by the β₃ receptor, without cardiac ortremor-related side effects.

SUMMARY OF THE INVENTION

The present invention encompasses novel compounds described by Formula Ibelow. ##STR2## wherein: X₁ is --OCH₂ --, --SCH₂ --, or a bond;

R₁ is a fused heterocycle of the formula: ##STR3## R₂ and R₃ areindependently H, C₁ -C₄ alkyl, or aryl; R₄ is an optionally substitutedheterocycle or a moiety selected from the group consisting of: ##STR4##X₂ is a bond, or a 1 to 5 carbon straight or branched alkylene; R₅ is H,or C₁ -C₄ alkyl;

R₆ is H, or C₁ -C₄ alkyl;

or R₅ and R₆ combine with the carbon to which each is attached to form aC₃ -C₆ cycloalkyl;

or R₆ combines with to X₂ and the carbon to which X₂ is attached to forma C₃ -C₈ cycloalkyl;

or R₆ combines with X₂, the carbon to which X₂ is attached, and R₄ toform: ##STR5## provided that R₅ is H;

R₇ is H, halo, hydroxy, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, aryl, CN, COOR₂,CONHR₂, NHCOR₂, OR₂, NHR₂, SR₂, SO₂ R₂, SO₂ NHR₂, or SOR₂ ;

R₈ is independently H, halo or C₁ -C₄ alkyl;

R₉ is halo, CN, OR₁₀, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, CO₂ R₂, CONR₁₁R₁₂, CONH(C₁ -C₄ alkyl or C₁ -C₄ alkoxy), SR₂, CSNR₂, CSNR₁₁ R₁₂, SO₂R₂, SO₂ NR₁₁ R₁₂, SOR₂, NR₁₁ R₁₂, optionally substituted aryl,optionally substituted heterocycle, or C₂ -C₄ alkenyl substituted withCN, CO₂ R₂ or CONR₁₁ R₁₂ ;

R₁₀ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, (CH₂)_(n) C₃ -C₈ cycloalkyl,(CH₂)_(n) aryl, (CH₂)_(n) heterocycle, (CH₂)_(n) C₃ -C₈ optionallysubstituted cycloalkyl, (CH₂)n optionally substituted aryl, (CH₂)_(n)optionally substituted heterocycle;

R₁₁ and R₁₂ are independently H, C₁ -C₄ alkyl, aryl, (CH₂)naryl, orcombine with the nitrogen to which each is bound to form morpholinyl,piperidinyl, pyrrolidinyl, or piperazinyl;

A₁ and A₂ are independently O, S, NH, CH₂, NCH₃, or NCH₂ CH₃ ;

m is 0 or 1;

n is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

The present invention also encompasses novel compounds described byFormula II below. ##STR6## wherein: R₁ is ##STR7## X₁ is --OCH₂ --,--SCH₂ --, or a bond; The bond between A₃ and A₄ is either a single ordouble bond;

A₃ and A₄ are independently carbon or nitrogen;

R₂ and R₃ are independently H, C₁ -C₄ alkyl, or aryl;

R₄ is an optionally substituted heterocycle or a moiety selected fromthe group consisting of: ##STR8## X₂ is a bond, or a 1 to 5 carbonstraight or branched alkylene; R₅ is H, or C₁ -C₄ alkyl;

R₆ is H, or C₁ -C₄ alkyl;

or R₅ and R₆ combine with the carbon to which each is attached to form aC₃ -C₆ cycloalkyl;

or R₆ combines with to X₂ and the carbon to which X₂ is attached to forma C₃ -C₈ cycloalkyl;

or R₆ combines with X₂, the carbon to which X₂ is attached, and R₄ toform: ##STR9## provided that R₅ is H; R₇ is H, halo, hydroxy, C₁ -C₄alkyl, C₁ -C₄ haloalkyl, aryl, CN, COOR₂, CONHR₂, NHCOR₂, OR₂, NHR₂,SR₂, SO₂ R₂, SO₂ NHR₂, or SOR₂ ;

R₈ is independently H, halo or C₁ -C₄ alkyl;

R₉ is halo, CN, OR₁₀, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, CO₂ R₂, CONR₁₁R₁₂, CONH(C₁ -C₄ alkyl or C₁ -C₄ alkoxy), SR₂, CSNR₂, CSNR₁₁ R₁₂, SO₂R₂, SO₂ NR₁₁ R₁₂, SOR₂, NR₁₁ R₁₂, optionally substituted aryl,optionally substituted heterocycle, or C₂ -C₄ alkenyl substituted withCN, CO₂ R₂ or CONR₁₁ R₁₂ ;

R₁₀ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, (CH₂)_(n) C₃ -C₈ cycloalkyl,(CH₂)_(n) aryl, (CH₂)_(n) heterocycle, (CH₂)_(n) C₃ -C₈ optionallysubstituted cycloalkyl, (CH₂)_(n) optionally substituted aryl, or(CH₂)_(n) optionally substituted heterocycle;

R₁₁ and R₁₂ are independently H, C₁ -C₄ alkyl, aryl, (CH₂)_(n) aryl orcombine with the nitrogen to which each is bound to form morpholinyl,piperidinyl, pyrrolidinyl, or piperazinyl;

m is 0 or 1;

n is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

The present invention also provides for novel intermediates, useful inthe preparation of compounds of Formulas I and II, described by FormulaIII below. ##STR10## wherein: A₅ is CH or N;

X₂ is a bond or a 1 to 5 carbon straight or branched alkylene.

R₅ is H, C₁ -C₄ alkyl;

R₆ is H, C₁ -C₄ alkyl;

or R₅ and R₆ combine with the carbon to which each is attached to form aC₃ -C₆ cycloalkyl;

or R₆ combines with X₂ and the carbon to which X₂ is attached to form aC₃ -C₈ cycloalkyl;

R₁₄ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, hydroxy, carboxy, tetrazolyl,acyl, COOR₂, CONR₁₁ R₁₂, CONH(C₁ -C₄ alkoxy), cyano, C₁ -C₄ alkoxy, C₁-C₄ alkyl, phenyl, nitro, NR₁₁ R₁₂, NHCO(C₁ -C₄ alkyl), NHCO(benzyl),NHCO(phenyl), SR₂, S(C₁ -C₄ alkyl), OCO(C₁ -C₄ alkyl), SO₂ (NR₁₁ R₁₂),SO₂ (C₁ -C₄ alkyl), or SO₂ (phenyl);

or pharmaceutically acceptable salts thereof.

The present invention also provides novel processes for making, as wellas novel pharmaceutical formulations of, compounds of Formulas I and II.

The compounds of the present invention are selective β₃ receptoragonists and as such are useful for treating Type II diabetes andobesity, as well as useful for agonizing the β₃ receptor. Therefore, thepresent invention also provides for methods of treating Type II diabetesand obesity, as well as a method of agonizing the β₃ receptor.

In addition, the present invention provides the use of compounds ofFormulas I and II for treating Type II diabetes and obesity as well theuse of compounds of Formulas I and II for agonizing the β₃ receptor.

Another representation of the compounds of the present invention isgiven by Formula IV below. ##STR11## wherein: R₁ is a fused heterocycleof the formula: ##STR12## R₂ is H, C₁ -C₄ alkyl, or aryl; R₃ is H, C₁-C₄ alkyl, aryl, or heterocycle;

R₄ is an optionally substituted heterocycle or a moiety selected fromthe group consisting of: ##STR13## R₅ is H, or C₁ -C₄ alkyl; R₆ is H, C₁-C₄ alkyl, bonds to X₂ to form a C₃ -C₈ cycloalkyl, or combines with X₂and R₄ to form: ##STR14## R₇ is H, halo, hydroxy, C₁ -C₄ alkyl, C₁ -C₄alkoxy, NH₂, SR₂, SO₂ R₂, or SOR2;

R₈ is independently H, halo or C₁ -C₄ alkyl;

R₉ is halo, CN, OR₁₀, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, CO₂ R₂, CONR₁₁R₁₂, CONH(C₁ -C₄ alkyl or C₁ -C₄ alkoxy), SR₂, CSNR₂, CSNR₁₁ R₁₂, SO₂R₂, SO₂ NR₁₁ R₁₂, SOR₂, NR₁₁ R₁₂, optionally substituted aryl,optionally substituted aryloxy, optionally substituted heterocycle, orC₂ -C₄ alkenyl optionally substituted with CN, CO₂ R₂ or CONR₁₁ R₁₂ ;

R₁₀ is independently C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, (CH₂)_(n) C₃ -C₈cycloalkyl, (CH₂)_(n) aryl, (CH₂)_(n) heterocycle, said aryl, C₃ -C₈cycloalkyl, or heterocycle being optionally substituted;

R₁₁ and R₁₂ are independently H, C₁ -C₄ alkyl, or combine with thenitrogen to which each are bound to form a morpholinyl, piperdinyl,pyrrolyl, or piperazine;

A₁ and A₂ are independently O, S, NH, or NCH₃ ;

X₁ is --OCH₂ --, --SCH₂ --, or absent;

X₂ is absent or a 1 to 5 carbon straight or branched alkylene;

m is 0 or 1;

n is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

DETAILED DESCRIPTION

For the purposes of the present invention, as disclosed and claimedherein, the following terms are defined below. As they relate to thepresent invention, the terms below may not be interpreted, individuallyor collectively, to describe chemical structures that are unstable orimpossible to construct.

The term "halo" represents fluorine, chlorine, bromine, or iodine.

The term "C₁ -C₄ alkyl" represents a cyclo, straight or branched chainalkyl group having from one to four carbon atoms such as methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyland the like. A "haloalkyl" is one such alkyl substituted with one ormore halo atoms, preferably one to three halo atoms. An example of ahaloalkyl is trifluoromethyl. An "alkoxy" is a alkyl group covalentlybonded by an --O-- linkage.

The term "1 to 5 carbon straight or branched alkylene" represents a oneto five carbon, straight or branched, alkylene moiety. A branchedalkylene may have one or more points of branching. A 1 to 5 carbonstraight or branched alkylene may optionally be unsaturated at one ormore carbons. Thus, a 1 to 5 carbon straight or branched alkyleneincludes 1 to 5 carbon alkylene, alkenylene and alkylidene moieties.Examples include methylene, ethylene, propylene, butylene, --CH(CH₃)CH₂--CH(C₂ H₅)CH₂ --, --CH(CH₃)CH(CH₃)--, --CH₂ C(CH₃)₂ --, --CH₂CH(CH₃)CH₂ --, --C(CH₃)₂ CH═, --CH═CHCH₂ --, --CH═CH--, and the like.

The "acyl" moiety, alone or in combination, is derived from an alkanoicacid containing from one to seven carbon atoms. The term "acyl" alsoincludes moieties derived from an aryl carboxylic acid.

The term "aryl" represents an optionally substituted or unsubstitutedphenyl or naphthyl. The term (CH₂)_(n) aryl is preferably benzyl orphenyl.

The notation "---" when used in conjunction with a bond indicates thatbond may either be a double bond or a single bond.

The term "optionally substituted" as used herein means an optionalsubstitution of one to three, preferably one or two groups independentlyselected from halo, C₁ -C₄ haloalkyl, hydroxy, carboxy, tetrazolyl,acyl, COOR₂, CONR₁₁ R₁₂, CONH(C₁ -C₄ alkoxy), cyano, C₁ -C₄ alkoxy, C₁-C₄ alkyl, phenyl, benzyl, nitro, NR₁₁ R₁₂, NHCO(C₁ -C₄ alkyl),NHCO(benzyl), NHCO(phenyl), SR₂, S(C₁ -C₄ alkyl), OCO(C₁ -C₄ alkyl), SO₂(NR₁₁ R₁₂), SO₂ (C₁ -C₄ alkyl), or SO₂ (phenyl); provided that suchsubstitution does not entirely destroy biological activity, as definedin this specification.

R₁₁ and R₁₂ are independently H, C₁ -C₄ alkyl, or combine with thenitrogen to which each is bound to form morpholinyl, piperidinyl,pyrrolidinyl, or piperazinyl.

The term "heterocycle" represents a stable, optionally substituted orunsubstituted, saturated or unsaturated 5 or 6 membered ring, said ringhaving from one to four heteroatoms that are the same or different andthat are selected from the group consisting of sulfur, oxygen, andnitrogen; and when heterocycle contains two adjacent carbon atoms, theadjacent carbon atoms may be structured to form a group of the formula--CH═CH--; provided that (1) when the heterocyclic ring contains 5members, the heteroatoms comprise not more than two sulfur or two oxygenatoms but not both; and (2) when the heterocyclic ring contains 6members and is aromatic, sulfur and oxygen are not present. Theheterocycle may be attached at any carbon or nitrogen which affords astable structure. The heterocycle may be optionally substituted.Examples of an heterocycle include pyrazole, pyrazoline, imidazole,isoxazole, triazole, tetrazole, oxazole, 1,3-dioxolone, thiazole,oxadiazole, thiadiazole, pyridine, pyrimidine, piperazine, morpholine,pyrazine, pyrrolidine, piperidine, oxazolidone, oxazolidinedione,imidazolidinone.

The term "leaving group" as used in the specification is understood bythose skilled in the art. Generally, a leaving group is any group oratom that enhances the electrophilicity of the atom to which it isattached for displacement. Preferred leaving groups are p-nitrobenzenesulfonate, triflate, mesylate, tosylate, imidate, chloride, bromide, andiodide.

The term "pharmaceutically effective amount", as used herein, representsan amount of a compound of the invention that is capable of agonizingthe β₃ receptor in mammals. The particular dose of the compoundadministered according to this invention will, of course, be determinedby the particular circumstances surrounding the patient, including thecompound administered, the route of administration, the particularcondition being treated, and similar considerations.

The term "unit dosage form" refers to physically discrete units suitableas unitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical carrier.

The term "treating," as used herein, describes the management and careof a patient for the purpose of combating the disease, condition, ordisorder and includes the administration of a compound of presentinvention to prevent the onset of the symptoms or complications, toalleviate symptoms or complications, or to eliminate the disease,condition, or disorder.

The term "agonizing," as used herein, means stimulating or affecting areceptor to elicit a pharmacological response.

The term "selective" means preferential agonism of the β₃ receptor overagonism of the β₁ or β₂ receptor. In general, the compounds of thepresent invention demonstrate at a minimum a twenty fold differential(preferably over a 50× differential) in the dosage required to behave asan agonist to the β₃ receptor and the dosage required for equal agonismof the β₁ and β₂ as measured in the Functional Agonist Assay. Thecompounds demonstrate this differential across the range of doses. Thus,β₃ selective compounds behave as agonists for the β₃ receptor at muchlower concentrations with lower toxicity by virtue of their minimalagonism of the other receptors.

As previously noted, the present invention provides a method of treatingtype II diabetes and obesity, comprising administering to a mammal inneed thereof compounds of the Formulas I and II. Preferred embodimentsof the present invention are set out in paragraphs below.

Preferred compounds are those of Formulas I and II, wherein:

(a) R₁ is ##STR15## (b) X₁ is --OCH₂ --, the oxygen of which is attachedto R₁. (c) X₁ is a bond.

(d) R₅ and R₆ are independently C₁ -C₄ alkyl.

(e) X₂ is isopropylene, ethylene, methylene, or a bond.

(f) R₄ is ##STR16## (g) R₄ is ##STR17##

Other preferred compounds are those of Formulas I and II, wherein:

(aa) R₁ is ##STR18## (bb) R₅ and R₆ are methyl or ethyl. (cc) X₂ ismethylene or ethylene.

(dd) R₈ is hydrogen.

(ee) R₈ is halo.

(ff) R₉ is OR₁₀.

(gg) R₉ is CONR₁₁ R₁₂.

(hh) R₉ is CN.

(ii) R₉ is optionally substituted aryl.

(jj) R₁₀ is (CH₂)_(n) aryl, (CH₂)_(n) heterocycle, (CH₂)_(n) optionallysubstituted aryl, or (CH₂)_(n) optionally substituted heterocycle.

More preferred compounds are those of Formula Ia, Ib, Ic, and Id:##STR19## Especially preferred compounds are those of Formulas Ia, Ib,Ic, or Id wherein: R₁ is ##STR20## X₁ is --OCH₂ -- the oxygen of whichis attached to R₁, R₃ is H, and R₉ is CONH₂ or OR₁₀, wherein R₁₀ is aoptionally substituted aryl, particularly phenyl, or optionallysubstituted heterocycle, particularly pyridine.

Other especially preferred compounds include the following:

(S, R and S, S)4-(3-[N-(2-[4-(5-carbamoyl-2-pyridyloxy)phenyl]-1-methylethyl)amino]-2-hydroxypropoxy)-1,3-dihydro-2H-benzimidazol-2-one

(S, R and S, S)5-(3-[N-(3-[2-oxo-1,3-dihydro-2H-benzimidazole-4-yloxy]-2-hydroxypropyl)amino]butyl)-2-thiophenesulfonamide

(S, R and S, S)4-(3-[N-(3-[4-(4-carbamoylphenoxy)phenyl]-1-methylpropyl)amino]-2-hydroxypropoxy)-1,3-dihydro-2H-benzimidazol-2-one

(All isomers of:)5-(4-[3-(N-[3-(2-oxo-1,3-dihydro-2H-benzimidazole-4-yloxy)-2-hydroxypropyl]amino)-2-methylbutyl]-3-fluorophenyl)-1H-tetrazole

(All isomers of:)4-(3-[N-(2-[(4-carbamoylphenyl)methyl]-1-methylpropyl)amino]-2-hydroxypropoxy)-1,3-dihydro-2H-benzimidazol-2-one

Most preferred comounds include the following structures: ##STR21##

By virtue of their acidic moieties, the compounds of Formulas I and IIinclude the pharmaceutical acceptable base addition salts thereof. Suchsalts include those derived from inorganic bases such as ammonium andalkali and alkaline earth metal hydroxides, carbonates, bicarbonates,and the like, as well as salts derived from basic organic amines such asaliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines,and the like. Such bases useful in preparing the salts of this inventionthus include ammonium hydroxide, potassium carbonate, sodiumbicarbonate, calcium hydroxide, methylamine, diethylamine,ethylenediamine, cyclohexylamine, ethanolamine and the like.

Because of the basic moiety, the compounds of Formulas I and II can alsoexist as pharmaceutically acceptable acid addition salts. Acids commonlyemployed to form such salts include inorganic acids such ashydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, aswell as organic acids such as para-toluenesulfonic, methanesulfonic,oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic,acetic acid, and related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate,phthalate, xylenesulfonate, phenylacetate, phenylpropionate,phenylbutyrate, citrate, lactate, hippurate, β-hydroxybutyrate,glycollate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the likesalts.

It is recognized that various stereoisomic forms of the compounds ofFormulas I and II may exist. The compounds may be prepared as racematesand can be conveniently used as such. Therefore, the racemates,individual enantiomers, diastereomers, or mixtures thereof form part ofthe present invention. Unless otherwise specified, whenever a compoundis described or referenced in this specification all the racemates,individual enantiomers, diastereomers, or mixtures thereof are includedin said reference or description.

It is also recognized that various tautomeric forms of the compounds ofFormulas I and II may exist, and all tautomeric forms are part of thepresent invention. Unless otherwise specified, whenever a compound isdescribed or referenced in this specification all tautomeric forms, ormixtures thereof, are included in said reference or description.

The compounds of Formulas I and II are prepared as described in thefollowing Schemes and Examples. Schemes 1 and 2 describe methodology forthe preparation of final embodiments of the present invention. Schemes3-5 describe methodology for the preparation of intermediates requiredfor the construction of the final embodiments of the invention.##STR22##

In Scheme I, X₁, X₂, R₁, R₂, R₄, R₅, and R₆ have the same meaning aspreviously described. The reaction of Scheme I is carried out underconditions appreciated in the art for the amination of epoxides. Forexample, the epoxide (A) may be combined with the amine (B) in analcohol, preferably, ethanol at room temperature to the refluxtemperature of the reaction mixture. Preferably, the reaction is carriedunder conditions generally described in Atkins et al., Tetrahedron Lett.27:2451 (1986). These conditions include mixing the reagents in thepresence of trimethylsilyl acetamide in a polar aprotic solvent such asacetonitrile, dimethylformamide (DMF), acetone, dimethylsulfoxide(DMSO), dioxane, diethylene glycol dimethyl ether (diglyme),tetrahydrofuran (THF), or other polar aprotic solvents in which thereagents are soluble. Preferably, the solvent is DMSO. The reaction iscarried out at temperatures ranging from about 0° C. to reflux.

Some of the compounds of the present invention are prepared by a novelcombinatorial/parallel synthesis. This synthesis is described in SchemeII. ##STR23##

In Scheme II, X₁, X₂, R₁, R₂, R₄, and R₅ have the same meaning aspreviously described. R₆ is H. The reaction of Scheme II is preferablycarried out by adding to a glass vial: a non-reactive solvent such asmethanol, DMF, methylene chloride or acetonitrile, amine (IV), andketone (V). The solution is shaken to allow for imine formation andtreated with Amberlite IRA400 borohydride resin (Aldrich). The slurry isthen shaken an additional 24 hours to effect reduction to the secondaryamine. Methylene chloride and polystyrene-linked benzaldehyde resin(Frechet, J. M. et al., J. Am Chem. Soc. 93:492 (1971)) is added to thevial, in order to scavenge excess primary amine starting material. Theslurry is shaken, preferably overnight. The slurry is then filteredthrough a cotton plug, and the residual solids rinsed with methanol.Evaporation under a flow of air, followed by drying for several hours atroom temperature in a vacuum oven yields the desired product ofsufficient purity.

A modification of Scheme II is necessary when the amine hydrochloridesalt is used. Addition of resin-bound base to the initial reactionmixture prior to reduction or scavenging allows the desired reaction toproceed. Imine formation using amine hydrochloride salts, an aldehyde orketone, and a resin bound amine base may be carried out using twodifferent resins: poly(4-vinylpyridine), commercially available fromAldrich, and resin (VIII), synthesized by the reaction of Merrifieldresin with piperidine (Scheme IIa): ##STR24##

In Scheme IIa, PS is polysytrene. Both the poly(4-vinylpyridine) andresin (VIII) promote imine formation.

Scheme II can also be carried out by utilization of traditional fashion.Reductive aminations described in scheme II are well known in the art.They are typically performed by mixing the amine and ketone startingmaterials in a solvent and adding a reducing agent. Solvents typicallyinclude lower alcohols, DMF, and the like. A wide variety of reducingagents can be utilized, most commonly utilized are sodium borohydrideand sodium cyanoborohydride. The reaction is typically performed at roomtemperature to the reflux temperature of the solvent. Products areisolated by techniques well known in the art.

The ketone and amino starting materials of Scheme II can be prepared bytechniques recognized and appreciated by one skilled in the art. Thesynthesis of the starting materials is generally described in SchemesIII and IV. ##STR25##

In Scheme III, R₁ is the same as previously defined. R₁₃ is OH or SH.Equimolar amounts of the aromatic compound (Compound IX) and(2S)-(+)-glycidyl 3-nitrobenzenesulfonate (Compound X) are dissolved inan inert solvent such as acetone and treated with 1.1 equivalents of anon-reactive acid scavenger, such as K₂ CO₃. The suspension is thenheated at reflux for 16-20 hours with stirring. The solvent is removedin vacuo. The residue is partitioned between chloroform or other organicsolvent and water. The organic layer is dried over Na₂ SO₄ andconcentrated in vacuo to give the epoxide (XI) in sufficient purity(>95%) and yield (85-100%).

The epoxide (XI) is dissolved in an alcohol, preferably methanol, andtreated with one equivalent of dibenzylamine. The solution is preferablystirred at reflux for three to four hours and then cooled to ambienttemperature. Approximately 10 equivalents of ammonium formate are addedto the flask, followed by 10% palladium on carbon, and the suspensionstirred vigorously at reflux for 30-45 minutes. The reaction mixture isthen filtered through Celite, concentrated in vacuo to a minimum volumeand treated with 1.1 equivalents of a 1.0 M anhydrous solution of HCl inether. The solution is concentrated to dryness. The solid residue istriturated with pentane to yield products of sufficient purity (>97%)and yield (60-100%). If desired, further purification may be carried outby passing over a short plug of silica, eluting with CHCl₃, then 95:5CHCl₃ /MeOH, the 25:5:1 CHCl₃ /MeOH/NH₄ OH.

Alternatively, the epoxide (XI) is treated with a solution of methanolsaturated with ammonia gas and stirred at room temperature in a sealedtube for 16 hours. This solution is then evaporated, and the residuesubjected to standard purifications such as column chromatography orrecrystallization. The HCl salt is then optionally produced by theaddition of HCl gas in ether.

The reaction of Scheme III is further described in Beedle et al., U.S.Pat. 5,013,761 and reference cited therein. U.S. Pat. 5,013,761 isherein incorporated by reference.

The ketone moieties of Scheme II, that are either unknown in the art ornot commercially available, are prepared in accordance with Scheme IV.##STR26##

In Scheme IV, R₄ and R₅ are the same as previously defined. The notation---- indicates optional branching. Preferably, R₄ is a substitutedphenyl. The reaction described in Scheme IV is referred to as a Heckreaction and is described in A.J. Chalk et al., J. Org. Chem. 41: 1206(1976). The reaction is achieved by treating compound (XIII) with anarylpalladium reagent. The arylpalladium reagent is generated in situ bytreating Compound (XIV) with a palladium-triarylphosphine complex. Thereaction is generally carried out in under conditions appreciated in theart.

Additional amines, of the type where X₂ is methylene, R₄ is aryl, andR₁₀ is aryl, heterocycle, optionally substituted aryl, or optionallysubstituted heterocycle, that are reacted in a manner analogous toScheme I are prepared in accordance with Scheme V. ##STR27##

Compounds of formula (XVII) can be prepared by reacting arylalkylalcohols of formula (XVI) with excess (5 mol/equiv) of a compound offormula (XVIA) by methods well known in the art. (see Sh. Prikl. Kin.,Vol 45, 1573-77 (1972); Russ). The reaction can also be carried out bymixing the reagents in an aprotic solvent, preferably diglyme, andadding potassium t-butoxide (0.5 mol/equiv.). The reaction is thenheated to reflux and water removed. After removal of water is complete,generally 2-8 hours depending upon the scale of the reaction, theresulting solution is subjected to aqueous workup including acidicwashes and the product is isolated by crystallization. Compounds offormula (XVIII) can be prepared by hydrogenation of the correspondingcompounds of formula (XVII) over a precious metal catalyst. Thehydrogenation can be affected at between 20 and 60 psi of hydrogen, andwith a variety of solvents, temperatures, and catalysts well known inthe art. The reaction is preferably carried out at 50 psi of hydrogenover 5% palladium on carbon wetted with 2B3 ethanol. Compound (XVII) ischarged to the reactor along with one equivalent of acetic acid, dilutedwith methanol, heated to 50 degrees °C., and subjected to hydrogen for5-24 hours depending on the scale of the reaction. The product isisolated as the acetic acid salt upon work up by methods well known inthe art.

A skilled artisan would appreciate that compounds of the formula (XVIII)could be coupled with a wide variety of aromatic halides to yield theclaimed ethers. The coupling can be carried out according to procedureswell known in the art and is preferably performed by mixing the startingmaterials in N,N-dimethylacetamide and toluene in the presence ofpotassium carbonate. The reaction is then heated to reflux for 5 to 24hours and water removed. The product is typically isolated by aqueouswork up after rotory evaporation of the reaction solvent. The crudeproduct can be purified by methods well know in the art. A skilledartisan would appreciate that the amines prepared by Scheme V can beutilized in Scheme I to prepare compounds of the present invention.Scheme V also describes preparation of novel intermediates of theFormula III. ##STR28## wherein: A₅ is CH or N;

X₂ is a bond or a 1 to 5 carbon straight or branched alkylene.

R₅ is H, C₁ -C₄ alkyl;

R₆ is H, C1-C₄ alkyl;

or R₅ and R₆ combine with the carbon to which each is attached to form aC₃ -C₆ cycloalkyl;

or R₆ combines with X₂ and the carbon to which X₂ is attached to form aC₃ -C₈ cycloalkyl;

R₁₄ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, hydroxy, carboxy, tetrazolyl,acyl, COOR₂, CONR₁₁ R₁₂, CONH(C₁ -C₄ alkoxy), cyano, C₁ -C₄ alkoxy, C₁-C₄ alkyl, phenyl, nitro, NR₁₁ R₁₂, NHCO(C₁ -C₄ alkyl), NHCO(benzyl),NHCO(phenyl), SR₂, S(C₁ -C₄ alkyl), OCO(C₁ -C₄ alkyl), SO₂ (NR₁₁ R₁₂),SO₂ (C₁ C₄ alkyl), or SO₂ (phenyl);

or pharmaceutically acceptable salts thereof.

Compounds of Formula III are useful in the preparation of compounds ofFormulas I and II, and as such represent an additional embodiment of thepresent invention.

Another embodiment of the present invention is a process of preparingnovel compounds of the formula IA ##STR29## wherein: A₅ is CH or N;

which comprises:

in step 1, hydrolysis of a compound of the formula IB: ##STR30## and instep 2, reacting the product of step 1 to form an acid addition salt.

Step one of the process can be carried out by a variety of agents knownin the art, it is however preferably affected by utilization of one ofthe following agents: polyphosphoric acid, H₂ O₂ and K₂ CO₃ indimethylsulfoxide, H₂ O₂ and ammonium hydroxide, H₂ O₂ and sodiumhydroxide, potassium hydroxide and t-butanol, or water and HCl. Step 2of the process involves the addition of an agent capable of forming anacid addition salt with the product of step 1. Step 2 can be carried outby numerous methods known in the art involving the addition of a mineralacid, or other acid, to a solution of the product of step 1.

Another embodiment of the present invention is a process of preparing acompound of Formulas I and II which comprises:

In step 1, reacting an epoxide of the formula (XI): ##STR31## with anamine of formula: ##STR32## and in step 2, reacting the product of step1 to form an acid addition salt.

The process can be carried out by a variety of agents known in the art,it is however preferably affected by reacting the amine and epoxide in asolvent at elevated temperature. Preferred solvents include: loweralcohols, dimethylformamide, dimethylsulfoxide, acetone and the like.The reaction is generally performed at a temperature ranging fromambient to the reflux temperature of the solvent. Most preferably, it isdone in ethanol at 40-60 °C. Step 2 can be carried out by numerousmethods known in the art involving the addition of a mineral acid, orother acid, to a solution of the product of step 1.

Starting materials for the compounds described in Schemes I, II, III, IVor V are either commercially available, known in the art, or can beprepared by methods known in the art or described herein.

PREPARATIONS AND EXAMPLES

The following examples and preparations are provided merely to furtherillustrate the invention. The scope of the invention is not construed asmerely consisting of the following examples. In the following examplesand preparations, melting point, nuclear magnetic resonance spectra,mass spectra, high pressure liquid chromatography over silica gel, gaschromatography, N,N-dimethylformamide, palladium on charcoal,tetrahydrofuran, ethyl acetate, thin layer chromatography and elementalanalysis are abbreviated M.Pt., NMR, MS, HPLC, GC, DMF, Pd/C, THF,EtOAc, TLC and EA respectively. The terms "EA", "TLC", "NMR", and "MS",when being utilized in the preparations, indicate that the dataindicated was consistent with the desired structure.

Preparations 1 through 18 encompass the methodology required to preparethe heterocyclic ethanol amines used in Scheme II to prepare finalembodiments of the invention.

Preparation 1 (S)-3-(2-Amino-3-nitrophenoxy)-1,2-epoxypropane

A solution of 2-amino-3-nitrophenol (5.95 g, 38.6 mmol) and(2S)-(+)-glycidyl 3-nitrobenzenesulfonate (10.0 g, 38.6 mmol) in 150 mLof acetone was treated with 1.1 equivalents of K₂ CO₃ (5.86 g, 42.4mmol) and stirred at reflux for 18 hours. The suspension was cooled toambient temperature; the solids were filtered; and the filtrateconcentrated in vacuo to dryness. The resulting solids were partitionedbetween chloroform and water, and the aqueous layer extracted once withchloroform. The organic layers were combined and dried over Na₂ SO4 andconcentrated in vacuo to 8.0 g (99%) of an orange solid. TLC (R_(f)=0.5, CHCl₃) and NMR indicated >95% purity, so the material was usedwithout further purification. NMR.

Preparation 2(S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-2-amino-3-nitrobenzene

(S)-3-(2-Amino-3-nitrophenoxy)-1,2-epoxypropane (8.0 g, 38.1 mmol) wasdissolved in 250 mL of methanol and treated with dibenzylamine (8.05 mL,42.0 mmol, d=1.026). The mixture was stirred at reflux for 10 hours andthen cooled to 0° C. The resulting orange precipitate was filtered andwashed with cold methanol, then dried to yield 12.1 g (78%) of a paleorange solid that was pure by NMR and TLC analysis. The material wasused without further purification. NMR.

Preparation 3 (S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-2,3-diaminobenzene

(S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-2-amino-3-nitrobenzene(10.6 g, 26.0 mmol) was suspended in 1 L of 2:1 ethanol/water at ambienttemperature and treated with excesses of sodium bicarbonate (26.22 g,0.31 mol) and sodium hydrosulfite (54.34 g, 0.31 mol). The orangereaction mixture slowly became colorless over 1 hour, and the mixturewas left to stir at ambient temperature for 16 hours. The suspension wasfiltered, and the filtrate concentrated in vacuo to a leave a whitesolid. This residue was partitioned between chloroform and water, andthe organic layer washed twice with brine. The combined organic extractswere concentrated in vacuo to give 8.8 g of a brown oil. The compoundwas recrystallized rapidly from toluene to give 7.96 g (81%) of palebrown needles. NMR.

Preparation 4(S)-4-[2-Hydroxy-3-(N,N-dibenzylamino)propoxy]-1,3-dihydro-2H-benzimidazol-2-one

(S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-2,3-diaminobenzene (4.4 g,11.6 mmol) was suspended in a mixture of toluene (60 mL) and 2N HCl (100mL) at ambient temperature with vigorous stirring. An excess oftriphosgene (17.3 g, 58.3 mmol) was added, and the stirring continuedfor 14 hours. The biphasic mixture was cautiously quenched andneutralized with sodium bicarbonate, causing an off-white precipitate toform at the interface. The precipitate was filtered and dried in vacuoto yield 4.35 g (93%) of a pale solid that was used without furtherpurification. TLC, NMR and MS all indicated high purity of theintermediate.

Preparation 5(S)-4-[2-Hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one##STR33##

(S) 4-[2-Hydroxy-3-(N,Ndibenzylamino)propoxy]-1,3-dihydro-2H-benzimidazol-2-one (4.35 g, 10.8mmol) was dissolved in methanol (200 mL) and treated with a vast excessof ammonium formate (13.0 g, 0.21 mol), followed by 10% palladium oncarbon (1.5 g). The suspension was stirred at reflux for 3 hours. Aftercooling the suspension, the reaction mixture was filtered throughCelite. The filtrate concentrated in vacuo to a pale brown oil whichslowly crystallized upon standing. The resulting solid was trituratedusing chloroform containing methanol and filtered to give 1.56 g (65%)as the desired product of a pale grey solid. NMR. MS.

Preparation 6 (S)-4-[2-(Dimethyl-tert-butylsilyl)oxy-3-(dibenzylamino)propoxy]benzimidazole

(S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-2,3-diaminobenzene (1 g,2.7 mmol) was dissolved in N,N Dimethylformamide (10 mL) and imidazole(0.27 g, 4.0 mmol) and tert-butyldimethylsilyl chloride (0.6 g, 4.0mmol) were added. The solution was stirred at ambient temperature for 18hours and then was partitioned between chloroform and water. Thecombined organic extracts were dried over sodium sulfate andconcentrated in vacuo to give the desired benzimidazole 1.3 g (96%).NMR.

Preparation 7(S)-4-[2-(Dimethyl-tert-butylsilyl)oxy-3-aminopropoxy]-benzimidazole##STR34##

(S)-4-[2-(Dimethyl-tert-butylsilyl)oxy-3-(dibenzylamino)propoxy]benzimidazole(1.27 g. 2.5 mmol) was dissolved in methanol (140 mL) and treated withan excess of ammonium formate (1.64 g, 25.0 mmol) followed by 10%palladium on carbon (410 mg). The resulting suspension was stirred atreflux for 1 hour. After cooling, the reaction mixture was filteredthrough a pad of celite. The filtrate was concentrated in vacuo to abrown oil (780 mg, 97%). NMR.

Preparation 8 (S)-4-[2-Hydroxy-3-aminopropoxy]benzimidazole ##STR35##

(S)-4-[2-(Dimethyl tert-butylsilyl)oxy-3-aminopropoxy]benzimidazole (10mg, 31 mmol) was dissolved in THF (1 mL) and the mixture cooled to 0 °C. Tetrabutylammonium fluoride (1 mL, 1.0 M solution in THF) was added.The reaction stirred at this temperature for 4 hours. The reaction wasquenched by addition of water. Evaporation of the aqueous layer providedthe desired alcohol. NMR. MS.

Preparation 9 (S)-3-(4-Amino-3-nitrophenoxy)-1,2-epoxypropane

A solution of 4-amino-3-nitrophenol (2.54 g, 16.5 mmol) and(2S)-(+)-glycidyl 3-nitrobenzenesulfonate (4.27 g, 16.5 mmol) in 50 mLof acetone was treated with 1.1 equivalents of K₂ CO₃ (2.50 g, 18.1mmol) and stirred at reflux for 20 hours. The suspension was cooled toambient temperature, concentrated in vacuo to dryness. The resultingsolids were partitioned between chloroform and water, and the aqueouslayer extracted with chloroform. The organic layers were combined anddried over MgSO₄ and concentrated in vacuo to provide 3.0 g (87%) of anorange solid. TLC and NMR indicated >95% purity, so the material wasused without further purification. NMR.

Preparation 10(S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-4-amino-3-nitrobenzene

The epoxide from preparation 9 (3.0 g, 14.3 mmol) was dissolved in 100mL of methanol and treated with dibenzylamine (3.02 mL, 15.7 mmol). Themixture was stirred at reflux for 6 hours and, after cooling, thesolvent was removed in vacuo. The resulting orange solid (5.8 g, 100%)was used without further purification. NMR.

Preparation 11 (S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-3,4-diaminobenzene

The nitroaniline from preparation 10 (4.89 g, 12.0 mmol) was suspendedin a mixture of ethanol (400 mL) and water (300 mL) at ambienttemperature and treated with sodium bicarbonate (12.1 g, 144 mmol, 12equiv.) and sodium hydrosulfite (25.1 g, 144 mmol, 12 equiv.) Thereaction mixture slowly became colorless over three hours. The reactionmixture was partitioned between chloroform and brine. The organic layerwas washed several times with brine, dried over magnesium sulfate andconcentrated in vacuo to give a brown oil. NMR.

Preparation 12 (S)-5-[2-Hydroxy-3-(N,Ndibenzylamino)propoxy]-1,3-dihydro-2H-benzimidazol-2-one

The diamine from Preparation 11 (2.1 g, 5.6 mmol) was suspended in amixture of toluene (40 mL) and 2N HCl (70 mL) at ambient temperaturewith vigorous stirring. An excess of triphosgene (17.3 g, 58.3 mmol) wasadded. The stirring continued for 14 hours. The biphasic mixture wascautiously quenched and neutralized with sodium bicarbonate, whichcaused an off-white precipitate to form at the interface. Theprecipitate was filtered and dried in vacuo to yield 1.06 g (47%) of agrey solid that was used without further purification. TLC, NMR and MSall indicated high purity of the intermediate.

Preparation 13(S)-5-[2-Hydroxy-3-amino)propoxy]-1,3-dihydro-2H-benzimidazol-2-one##STR36##

The compound from preparation 12 (0.75 g, 1.9 mmol) was dissolved inmethanol (100 mL) and treated with an excess of ammonium formate (0.7 g,11.2 mmol), followed by 10% palladium on carbon (400 mg). The suspensionwas stirred at reflux for 3 hours. After cooling the suspension, thereaction mixture was filtered through celite and the filtrateconcentrated in vacuo to a greyish black solid (0.25 g, 60%). NMR. MS.

Preparation 14 (S)-5-[2-(Dimethyl tert-butylsilyl)oxy-3-(dibenzylamino)propoxy]benzimidazole

This compound was prepared in a manner analogous to Preparation 6. NMR.MS.

Preparation 15 (S)-5-[2-(Dimethyl-tert-butylsilyl)oxy-3-aminopropoxy]-benzimidazole

This compound was prepared in a manner analogous to Preparation 7. NMR.MS.

Preparation 16 (S)-4-[2-Hydroxy-3-amino propoxy]benzimidazole ##STR37##

The desired aminoalcohol was prepared in a manner similar to Preparation8. NMR. MS.

Preparation 17 4-[(2S)-2,-3-oxo-propoxy]-2(3H)benzoxazolone

A solution of 4-Hydroxy-2(3H)benzoxazolone (1.00 g, 6.6 mmol) and(2S)-(+)-glycidyl 3-nitrobenzenesulfonate (1.72 g, 6.6 mmol) in 50 mL ofacetone was treated with 1.1 equivalents of K₂ CO₃ (1.01 g, 7.3 mmol)and stirred at reflux for 4 hours. The suspension was cooled to ambienttemperature, the solvent concentrated in vacuo to dryness. The resultingsolids were partitioned between chloroform and water, and the aqueouslayer extracted once with chloroform. The organic layers were combinedand dried over Na₂ SO₄ and concentrated in vacuo to give a white solid.Flash chromatography (chloroform/methanol 9/1) provided themonoalkylated product (0.55 g, 40%). NMR. MS.

Preparation 18 (S)-4-[2-Hydroxy-3-aminopropoxy]-2(3H)benzoxazolone##STR38##

A solution of 4-[(2S)-2, 3-oxo-propoxy]-2(3H)benzoxazolone (0.15 g, 0.72imol) in methanol (2 mL) was cooled to -78° C. using a dry ice/acetonebath. Ammonia gas (2 mL) was condensed into the reaction mixture. Thereaction vessel was capped and allowed to warm slowly to roomtemperature overnight. The reaction was quenched by uncapping thereaction vessel and allowing the ammonia gas to evaporate. NMR. MS.

Preparation 19(S)-4-(4-[2-(N-[3-(2-amino-3-nitrophenoxy)-2-hydroxypropyl]amino)-2-methylpropyl]phenoxy)benzamide##STR39##

A suspension of (S)-3-(2-amino-3-nitrophenoxy)-1,2-epoxypropane (5 g,23.8 mmol) and 4-(4-(2-amino-2-methylpropyl)phenoxy)benzamide (20.3 g71.1 mmol) in absolute ethanol (200 mL) was heated to 55° C. for 12 h.All solids went into solution at 50° C. Upon completion of the reaction,the solvent was evaporated to dryness. The residue was redissolved inethyl acetate and washed with a saturated solution of sodiumbicarbonate. The layers were separated and the aqueous phase wasextracted with ethyl acetate. The two organic layers were combined andwashed with brine. The phases were separated and the organic layer wasdried over sodium sulfate, filtered, and the solvent evaporated. Columnchromatography eluting with 20% MeOH/CHCl₃ gave 7.26 g (62%) of product.NMR. MS.

Preparation 20(S)-4-(4-[2-(N-[3-(2,3-diaminophenoxy)-2-hydroxypropyl]amino)-2-methylpropyl]phenoxy)benzamide##STR40##

The nitroaniline from preparation 19 (0.484 g, 0.98 mmol) was dissolvedin absolute ethanol (40 mL) and treated with a solution of sodiumbicarbonate (0.50 g, 5.95 mmol) in water (10 mL) followed by a solutionof sodium hydrosulfite (1.41 g, 8.1 mmol) in water (15 mL). Once thecolor had completely diminished, the solvents were evaporated. Theresidue was washed with water to remove excess salts. The leftoveramorphous material was dissolved in methanol and gravity filtered. Thesolvent was evaporated to give 0.454 g (100%) of product. NMR. MS.

Preparation 21 4-t-butyldimethylsilyloxyindole

A solution of 4-hydroxyindole (3.0 g, 22.5 mmol), t-butyldimethylsilylchloride (5.09 g, 33.8 mmol) and imidazole (3.83 g, 56.3 mmol) indimethylformamide (60 mL) was stirred at room temperature for 24 hours.Aqueous ammonium chloride was added (100 ml) and extracted several timeswith ethyl acetate. The organic layers were combined, dried overmagnesium sulfate, and evaporated to give a crude oil. Flashchromatography (10% ethyl acetate/hexanes) yielded the desired product(5.55 g, 100%) as a white solid. NMR.

Prepartion 22 4-t-butyldimethylsilyloxy-2-phenylindole

4-t-Butyldimethylsilyoxyindole (4.67 g, 18.9 mmol) was dissolved in THF(100 ml) at -78° C. under a nitrogen atmosphere and treated withbutyllithium (13.0 ml, 1.6 M in hexanes, 20.8 mmol) dropwise over 10minutes. After stirring for 30 minutes, carbon dioxide gas was passedthrough the solution for 20 minutes. The clear solution was allowed towarm to room temperature and vigorous effervescence was observed. Theexcess carbon dioxide was removed under vacuum on a rotary evaporator atroom temperature while the solvent was concentrated to an approximately50 ml volume. Additional THF (60 mL) was added and the solution wascooled to -78° C. To this mixture, t-butyllithium (12.2 ml, 20.8 mmol)was added dropwise over 10 minutes, and the mixture stirred for 2 h at-78° C. Tributyltin chloride (5.4 ml, 19.8 mmol) was added dropwise.After stirring for 1.5 h, the cold solution was poured over crushedice-water (100 g), and saturated ammonium chloride was added untilsolution became acidic. The aqueous solution was extracted with ether(3×100 ml), dried over magnesium sulfate, and concentrated to give 12.68g of a yellow oil.

To a solution of this 1-carboxy-2-(tributylstannyl)indole (12.68 g) inethanol (100 ml) was added iodobenzene (2.1 ml, 18.9 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.60 g, 0.85 mmol). Themixture was maintained at reflux for 48 h. The mixture was cooled toroom temperature, filtered through a pad of celite, and concentrated atreduced pressure. Flash chromatography (5% ethyl acetate/hexanes)provided the 4-t-butyldimethylsilyloxy-2-phenylindole as a white solid.NMR. MS.

Preparation 23 4-hydroxy-2-phenylindole

4-t-Butyldimethylsilyoxy-2-phenylindole (55 mg, 0.17 mmol) was dissolvedin THF (10 ml) at 0° C. and treated with tetrabutylammonium flouride(0.5 ml, 1.0 M in THF, excess). After stirring at this temperature for10 minutes, the reaction was quenched by addition of saturated ammoniumchloride. The mixture was extracted several time with ethyl acetate,dried over magnesium sulfate, and evaporated to give a crude oil. Flashchromatography (5% ethyl acetate/hexanes) provided the desired phenol(30 mg, 84.8%) as a white solid. NMR. MS.

Preparations 24 through 37 describe syntheses of compounds utilized incombinatorial/parallel scheme II.

Preparation 24 4-(3-oxobutyl)-1-(2-oxazolidine)benzene ##STR41##

4-bromo-1-(2-oxazolidine)benzene (3.0 g, 13.3 mmol), 3-buten-2-ol (1.4g, 20 mmol), Pd(OAc)₂ (60 mg, 0.26 mmol), (o-tolyl)₃ P (158 mg, 0.52mmol), sodium bicarbonate (1.34 g, 15.9 mmol) in 30 mL ofN-methylpyrrolidinone was heated under nitrogen at 130° C. for 1 hour.The reaction mixture was then cooled and was partitioned between ethylacetate and water. The combined organic layers were washed with waterand then dried (Na₂ SO₄), filtered and concentrated in vacuo to yield2.6 g of a tan oil. Purification by flash chromatography (silica gel,1:1 ethyl acetate/hexane) yielded 1.9 g of a pale yellow oil whichcrystallized upon drying under vacuum. Recrystallization from hexanegave 1.47 g (49%) of white needles, m.p. 62-64° C. NMR. MS.

Preparation 24 4-[4-(3-oxobutyl)phenoxy]benzonitrile ##STR42##

4-fluorobenzonitrile (6.05 g, 50 mmol), 4-(4-hydroxyphenyl)-2-butanone(8.21 g, 50 mmol) and potassium carbonate (8.3 g, 60 mmol) weredissolved in N,N-dimethylacetamide (50 mL) and heated at 150° C. for 4hours under nitrogen. The reaction mixture was then poured into 800 mLof ice water. A slowly crystallizing solid was filtered to give 13 g ofcrude product. This material was recrystallized from ethanol/water (3:1)to give 10.48 g (79%) of pale brown crystals, m.p. 64-66° C. EA. NMR.MS.

Preparation 25 [4-(3-oxobutyl)phenoxy]benzamide ##STR43##

4-[4-(3-oxobutyl)phenoxy]benzonitrile (6.0 g, 22.6mmol) and potassiumcarbonate (1.0 g, 7.2 mmol) were slurried in DMSO (50 mL) and cooled to0° C. in an ice bath. Aqueous 30% hydrogen peroxide (6 mL) was addedslowly, and the mixture stirred at 0° C. for 1 hour. The reaction wasquenched by pouring into 500 mL water, and the subsequent whiteprecipitate was collected and washed with water. This material wasrecrystallized from 300 mL ethanol to give 5.35 g (84%) white crystals,m.p. 169-172° C. NMR. MS. EA.

Preparation 26 2-triphenylmethyl-5-chloromethyltetrazole

5-Chloromethyltetrazole (1.19 g, 10 mmol) in CH₂ Cl₂ (10 mL) was treatedwith triphenylmethyl chloride (2.79 g, 10 mmol) anddiisopropylethylamine (2.0 mL, 11.5 mmol) and stirred for 40 minutes atroom temperature. The reaction mixture was concentrated in vacuo andpartitioned between ethyl acetate/water. The organic layer was washedwith saturated NaHCO₃ solution, then brine, dried (Na₂ SO₄) andconcentrated in vacuo to yield 3.48 g of an off-white solid. Triturationof this residue in diethyl ether yielded 3.04 g (84%) of a white solid,m.p.162-165° C. NMR. MS. EA.

Preparation 27 5-[4-(2-oxobutyl)phenoxymethyl]tetrazole ##STR44##

4-(4-hydroxyphenyl)-2-butanone (493 mg, 3 mmol) was cooled to 5° C. andtreated with NaH (180 mg, 4.5 mmol, 60% in mineral oil) under nitrogen.After 15 minutes the ice bath was removed and the solution allowed towarm to room temperature over 45 minutes. The reaction was cooled to 5°C. and treated with 2-triphenylmethyl-5-chloromethyltetrazole (1.08 g, 3mmol) and stirred at room temperature for 3 hours. The reaction mixturewas poured into EtOAc (300 mL), and washed with water then brine. Theorganic layer was dried (MgSO₄) and concentrated in vacuo to provide ayellow solid. This material was suspended in a mixture of MeOH (100 mL)and THF (50 mL) and treated with 4N HCl in dioxane (7.5 mL, 30 mmol).The resulting mixture was stirred for 1.5 hr. and then concentrated invacuo to provide a tan solid. The residue was applied to a silicachromatography column and eluted with 33-100% ethyl acetate in hexane toprovide 235 mg (32%) of a white solid, m.p.148-150° C. NMR. MS. EA.

Preparation 28 3-[4-(2-oxobutyl)phenoxymethyl]pyridine ##STR45##

4-(4-hydroxyphenyl)-2-butanone (4.11 g, 25 mmol) and potassium carbonate(10.37 g, 75 mmol) in acetone (30 mL) was treated with 3-picolylchloride hydrochloride (4.27 g, 26 mmol) under nitrogen. The mixture wasstirred at reflux for 21 hours, proceeding about 50% towards completion.Potassium iodide (2.0 g, 13 nmol, 0.5 eq) was added and after 3 hours nopicolyl chloride was observed on TLC. The volatiles were removed invacuo and the resulting residue partitioned between EtOAc/water. Thecombined organic layers were washed with water, saturated NaHCO₃solution, 10% Na₂ SO₃, and then brine. The organic layer was dried(MgSO₄) and concentrated in vacuo to provide 4.8 g of a yellow oil. Thematerial was purified on a Waters Prep 2000LC by elution with 10-80%ethyl acetate in hexanes over 45 minutes to yield 2.20 g (34%) of an oilwhich solidified on standing, m.p. 35-37° C. NM. MS. EA.

Preparation 29 2,6-dimethoxy-4-[4-(2-oxobutyl)phenoxy]-1,3,5-triazine##STR46##

4-(4-hydroxyphenyl)-2-butanone (4.93 g, 30 mmol) was added to a solutionof sodium methoxide (1.62 g, 30 mmol) in methanol (150 mL) undernitrogen. After stirring for 1 hour the methanol was removed in vacuoand the residue suspended in acetone (200 mL). The suspension wastreated with 4,6-dimethoxy-2-chlorotriazine and refluxed for 3 hours.The volatiles were removed in vacuo and the residue partitioned betweenethyl acetate/water. The organic layers were dried (MgSO₄) andconcentrated in vacuo to provide 10.28 g of a white semi-solid. Thematerial was purified on a Waters Prep 2000 LC by elution with agradient of 20-60% ethyl acetate in hexanes over 55 minutes to yield4.43 g (49%) of a colorless oil. NMR. MS. EA.

Preparation 30 2-[4-(2-oxobutyl)phenoxy]-5-carboxamidopyridine ##STR47##

4-(4-hydroxyphenyl)-2-butanone (3.28 g, 20 mmol) in anhydrous DMF (150mL) was treated with NaH (1.2 g, 30 mmol, 60% in mineral oil) undernitrogen. The solution was stirred for 30 minutes at ambient temperatureand then treated with 6-chloronicotinamide (3.13 g, 20 mmol). Thereaction was stirred at 60° C. for 1.5 hours and then 90° C. for fivehours. The reaction was allowed to cool, poured into 50% saturatedammonium chloride solution, and extracted with EtOAc. The organic layerwas dried (MgSO₄) and concentrated in vacuo with a xylene azeotrope toyield 11.4 g of a brown oil. The material was purified on a Waters Prep2000 LC by elution with 75-100% EtOAc over 60 minutes. The resultingmaterial was triturated in cold EtOAc and collected by filtration toprovide 2.73 g (48%) white solid m.p. 137-139° C. EA. NMR. MS.

Preraration 31 2-[4-(2-oxopropyl)phenoxy]-5-carboxamidopyridine##STR48##

In a manner similar to the above examples,3-(4-hydroxyphenyl)-2-propanone (2.25 g, 15 mmol) was treated with NaH(0.9 g, 22.5 mmol, 60% in mineral oil) followed by reaction with6-chloronicotinamide (2.34 g, 15 mmol). Following workup the materialwas purified on a Waters Prep 2000 LC to provide 1.28 g (32%) of a lightyellow solid. m.p. 172-174° C. NMR. MS. EA.

Preparation 32 {4-[(2-oxocyclohexyl)methyl]phenyl}methanenitrile##STR49##

A mixture of methyl cyclohexanone-2-carboxylate (11.0 g, 70 mmol, fromFluka), α-bromo-p-tolunitrile (12.3 g, 63 mmol), potassium carbonate(10.5 g, 76 mmol) in THF (200 mL) was refluxed for 24 hours. Theprogress of the reaction was followed by GC. The reaction was dilutedwith water and the THF was removed under reduced pressure. The aqueousportion was extracted with EtOAc, dried (MgSO₄) to give 19.3 g of awhite solid that was 74% pure by gas chromatrophy. The solid wasrecrystallized from hexane/EtOAc to give 7.75 g white crystals that were100% pure by glc. A second crop of 3.65 g was obtained by adding morehexane to the filtrate. Overall, 11.4 g (67%) of1-[(4-cyanophenyl)methyl]-1-methoxycarbonyl-2-oxocyclohexanecarboxylate, was obtained; mp 82-84° C. NMR. MS.

Under a blanket of nitrogen, a mixture of1-[(4-cyanophenyl)methyl]-1-methoxycarbonyl-2-oxocyclohexane carboxylate(7.6 g, 28 mmol), sodium cyanide (2.1 g, 42 mmol) and DMSO (100 mL) washeated at 115° C. for 1.5 hours. The progress of the reaction wasmonitored by gc. The reaction was cooled and partitioned between water,EtOAc and brine. The organic layer was washed with water and dried(MgSO₄). After concentration, crude product was obtained as a tan oil.Purification by plug filtration (200 g silica gel, 15% EtOAc/hexane)gave 3.3 g (55%) product as colorless oil. NMR. MS.

Preparation 33 4-[(2-oxocyclohexyl)methyl]benzamide ##STR50##

A DMSO (20 mL) solution of the compound of Preparation 28 (2.5 g, 11.7mmol) was cooled in an ice bath. Solid K₂ CO₃ (500 mg) was addedfollowed immediately by 30% H₂ O₂ (3 mL). After 20 minutes, TLC (3/7EtOAc/hexane) showed a trace of starting material remained. The ice bathwas removed and the reaction was stirred and room temperature for 1hour. The reaction was diluted with 500 mL water and the white solidcollected and dried to give 2.44 g (90%) desired amide. The product wasrecrystallized from 1/9 EtOAc/hexane to give 2.02 g of the titledproduct as white crystals, mp 167-170° C. NMR. MS.

Preparation 34 2-Tetralone-6-carboxylic acid, ethylene ketal

6-bromo-2-tetralone (2.0 g, 8.89 mmol) was dissolved in toluene (50 mL)and treated with excess ethylene glycol (4.88 mL, 88.9 mmol) andcatalytic p-toluenesulfonic acid (15 mg). The solution was stirred atreflux 16 hours, and water was removed from the reaction mixture using aDean-Stark condenser. After cooling to ambient temperature, the toluenesolution was washed 2×1N NaOH, 1×water, 1×brine, dried over Na₂ SO₄ andconcentrated in vacuo to give 2.23 g (93%) of 6-bromo-2-tetraloneethylene ketal as a brown oil which was used without furtherpurification.

6-Bromo-2-tetralone ethylene ketal (2.2 g, 8.15 mmol) was dissolved inanhydrous THF (30 mL), cooled to -78° C. and treated withtert-butyllithium (12.05 mL, 20.4 mmol, 1.7M in pentane) under anatmosphere of nitrogen. After stirring for 30 minutes, anhydrous carbondioxide gas was passed through the reaction mixture for 20 minutes at-78° C. The suspension was then allowed to warm to ambient temperature.The solution was quenched with water and acidified with 1N HCl, thenextracted 2×EtOAc. The organic extracts were washed with brine, driedover Na₂ SO₄ and concentrated in vacuo to a pale brown oil. The oilyresidue was applied to a silica flash chromatography column and elutedwith 30%-50% EtOAC in hexanes to yield tetralone-6-carboxylic acid,ethylene ketal 1.06 g (55%) of a slowly crystallizing solid. NMR. MS.

Preparation 35 2-Tetralone-6-carboxamide ##STR51##

Tetralone-6-carboxylic acid, ethylene ketal (395 mg, 2.07 mnmol) wasco-dissolved in CH₂ Cl₂ (50 mL) with N-hydroxysuccinimide (260 mg, 2.76mmol) at 0° C. and treated with a slight excess of1,3-dicyclohexylcarbodiimide (502 mg, 2.50 mmol). The mixture wasallowed to warm to ambient temperature over 30 minutes, during whichtime a fine white precipitate formed. Ammonium chloride (333 mg, 6.23mmol) and triethylamine (1.58 mL, 12.5 mmol, d=0.797) were added. Thesolution was stirred at ambient temperature for 16 hours. The suspendedurea and salts were filtered away and the solution concentrated in vacuoto a colorless oil. The oil was applied to a silica flash chromatographycolumn and eluted with 50-100% EtOAc in hexanes to yield 250 mg (64%) of2-tetralone-6-carboxamide, ethylene ketal as a white solid, clean byNMR, TLC.

2-Tetralone-6-carboxamide ethylene ketal (250 mg, 1.07 mmol) andcatalytic p-toluenesulfonic acid were stirred in acetone (50 mL) atambient temperature for 48 hours. The volatiles were removed in vacuoand the residue triturated in ethyl acetate. The solids were filtered,washed and dried to yield 77.5 mg (38%) of 2-Tetralone-6-carboxamide asa white powder, pure by NMR, TLC. MS.

Preparation 36 2-Tetralone-6-morpholinamide ##STR52##

2-Tetralone-6-carboxylic acid, ethylene ketal (395 mg, 2.07 mmol) wascodissolved in CH₂ Cl₂ (50 mL) with N-hydroxysuccinimide (260 mg, 2.76mmol) at 0° C. and treated with a slight excess of1,3-dicyclohexylcarbodiimide (502 mg, 2.50 nmol). The mixture wasallowed to warm to ambient temperature over 30 minutes, during whichtime a fine white precipitate formed. Morpholine (0.91 mL, 10.4 mmol,d=0.998) was added and the solution stirred at ambient temperature for16 hours. The suspended urea was filtered away and the solutionconcentrated in vacuo to a colorless oil. The oil was applied to asilica flash chromatography column and eluted with 50-100% EtOAc inhexanes to yield 323 mg (51%) of 2-tetralone-6-morpholinamide, ethyleneketal as a slowly crystallizing solid, clean by NMR, TLC.

2-Tetralone-6-morpholinamide, ethylene ketal (323 mg, 1.06 mmol) andcatalytic p-toluenesulfonic acid were stirred in acetone (50 mL) atambient temperature for 48 hours. TLC indicated a mixture of2-tetralone-6-morpholinamide, ethylene ketal and desired product, so thesolution was heated to reflux for 16 hours. The volatiles were removedin vacuo and the residue applied to a silica flash chromatography columnand eluted with 50-100% EtOAc in hexanes to yield 27 mg (10%) of2-tetralone-6-morpholinamide a slowly crystallizing solid, pure by NMR,TLC. MS.

Preparation 37 (R)4-[2-Hydroxy-3-(N,N-dibenzylamino)propoxy]-1,3-dihydro-2H-benzimidazol-2-thione##STR53##

[3-(N,N-Dibenzylamino)-2hydroxypropoxy]-2,3-diamino benzene (400 mg, 1.1mmol) was dissolved in a mixture of methylene chloride (70 mL) andpyridine (35 mL) and cooled to 0° C. Dimethylamino pyridine (DMAP; 311mg, 2.5 mmol) was added and thiophosgene (179 mg, 0.119 mL, 1.6 mmol)was introduced in a dropwise fashion. After 30 minutes, anotherequivalent of thiophosgene was added and the mixture was stirred for 5hours. Water was carefully added and the resulting biphasic mixtureextracted with methylene chloride. The organic solution was dried overMgSO₄ and, filtered and evaporated to leave a brown oil (445 mg, ca.100%). MS, NMR.

The above titled compound is converted to the amine for reaction inaccordance with Scheme 1 by techniques appreciated in the art.

Preparation 38 4-(2-Methyl-2-nitropropyl)phenol ##STR54##

A mixture of 4-hydroxybenzyl alcohol (100.08 g, 806 mmol),2-nitropropane (400 mL, 4.45 mol) and diglyme (800 mL) was heated to 38°C. Potassium t-butoxide (45.29 g, 403.6 mmol) was added, and the mixturewas heated to reflux at 132° C. with a Dean-Stark trap. Water begancollecting in the trap, and continued at a high rate for approximately1.5 h. When water collection slowed (around 2.5 h) then portions ofsolvent (30-40 mL each) were removed every thirty minutes. During thewater collection and solvent removal the temperature rose from 132° C.to 149° C. After 4 h less than 1% of the 4-hydroxybenzyl alcoholremained by HPLC analysis. The heating mantle was removed, and thereaction mixture was allowed to cool. When the temperature was 100° C.water (200 mL) was added, and the solution was allowed to cool to roomtemperature. Solvent was removed on a rotary evaporator under vacuumuntil 593 g of solution remained. Water (500 mL) and EtOAc (500 mL) wereadded and the layers were separated (layer separation was poor, butaddition of 20% aqueous NaCl was ineffectual). The aqueous layer wasextracted with EtOAc (200 mL), and the combined organic layers wereextracted with 1N HCl (500 mL) and water (300 mL). The organic layer wasdistilled in vacuo to 261 g of oil to which EtOAc was added (160 ML).Heptane (3.4 L) was added rapidly with vigorous stirring for 30 min, andthe product crystallized to yield a beige solid (112.36 g, 71%yield, >98% purity by HPLC analysis). Another crop of crystals may beobtained from the filtrate by concentrating and filtering the solids, orby concentrating more fully to a solution and adding heptane tocrystallize. NMR. E.A.

Preparation 39 4-(2-amino-2-methylpropyl)phenol acetic acid salt##STR55##

A one-gallon high-pressure reactor was charged with4(2-methyl-2-nitropropyl)phenol (120 g, 614 mmol), HOAc (35.2 mL, 614mmol), 5% Palladium on carbon (24 g) wetted with 2B3 EtOH (60 mL), andMeOH (1230 mL). The mixture was heated to 50° C. with agitation (600rpm), and the reactor was purged with N₂ and pressurized to 50 psi withH₂. After 15.5 h the reactor was purged with N₂, and the cooled mixturewas filtered. The filter cake was washed with MeOH and the filtrate wasconcentrated to 514 g of slurry on a rotary evaporator. To this slurrywas added EtOAc (2 L) with vigorous agitation. After stirring for 1 h,the resulting crystals were filtered and washed with a small amount ofEtOAc. The product was dried overnight in a 45° C. vacuum oven to yield118.83 g (86%) of product as small white needles (mp 211-216° C. dec).This material was 99% pure by HPLC analysis, and while another 9.00 g ofmaterial was obtained from the mother liquor it was found to be only 88% pure.

Preparation 402-(4-(2-amino-2-methylpropyl)phenoxy)-5-carboxamidopyridine ##STR56##

A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (45.06 g,200 mmol), powdered K₂ CO₃ (69.1 g, 500 mmol), 6-chloronicotinamide(31.32 g, 200 mmol), DMAC (622 mL) and iso-octane (70 mL) was slowlyheated to reflux at 140° C. A water trap filled with iso-octane was usedto collect water formed in the reaction, and reflux was maintained for5.5 h. The mixture was allowed to cool to room temperature, and thesolids were filtered and washed with EtOAc. The filtrate wasconcentrated in vacuo to 88.6 g of solid which was dissolved in EtOAc(500 mL). To this solution was added water (800 mL), 1N HCl (200 mL) andMeOH (50 mL). The pH of this mixture was adjusted to 7.2 with con. HCl,and the aqueous layer was separated and washed with methyl t-butyl ether(500 mL). The product was crystallized by addition of 10N NaOH (20 mL)which raised the pH to 11. This pH was maintained by addition of 10NNaOH as needed during the course of the crystallization (90 min). Theproduct was filtered, washed with water and dried in vacuo at 45° C. to53.11 g (93%) of white solid which was >98% pure by HPLC analysis: ¹ HNMR (300 MHz, DMSO-d₆) NMR was consistent with the desired product;

Preparation 41 4-(4-(2-amino-2-methylpropyl)phenoxy)benzonitrile##STR57##

A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (45.06 g,200 mmol), powdered K₂ CO₃ (69.1 g, 500 mmol), and DMAC (550 mL) washeated to 75-100° C. Toluene (166 mL) was added, and the mixture wasslowly heated to reflux at 134° C. The reflux temperature was raised bydistillation of toluene and water into a water trap until thetemperature reached 141° C. The mixture was then allowed to cool tobelow 100° C. at which point 4-fluorobenzonitrile (24.46 g, 202 mmol)was added along with 50 mL of toluene. The mixture was again heated toreflux at 140° C. with water being collected in a toluene-filled watertrap for 4 h. The mixture was allowed to cool to room temperature, andthe solids were filtered and rinsed with toluene. The filtrate wasconcentrated on a rotary evaporator to 77 g of syrup which was dissolvedin EtOAc (400 mL). This solution was extracted with water (400 mL), andthe aqueous layer was back-extracted with EtOAc (100 mL). The combinedorganic layers were washed with water (3×400 mL) and concentrated invacuo to 53.4 g (100%) of oil which was >98% pure by HPLC analysis: ¹ HNMR (300 MHz, DMSO-d₆) NMR was consistent with the desired product;

Preparation 42 4-(4-(2-amino-2-methylpropyl)phenoxy)benzamide ##STR58##

Aqueous 30% H₂ O₂ (62.1 mL, 548 mmol) was added dropwise to a mixture of4-(4-(2-amino-2-methylpropyl)phenoxy)benzonitrile (53.2 g, 200 mmol), K₂CO₃ (15.78 g, 114 mmol) and DMSO (270 mL) over 20 min while thetemperature was held at 20° C. with a cooling bath. The mixture wasstirred at this temperature for 1 h after the addition was complete, andthen water (209 mL) was added slowly. The slurry was cooled in an icebath with stirring for 1 h, and the product was then filtered, washedwith water and dried in vacuo at 50° C. to yield 55.0 g (97%) of whitesolid. Analysis by HPLC indicated purity of >99%: ¹ H NMR (300 MHz,DMSO-d₆) NMR was consistent with the desired product;

Preparation 432-(4-(2-amino-2-methylpropyl)phenoxy)-5-carbonitrilepyridine ##STR59##

A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (22.53 g,100 mmol), powdered K₂ CO₃ (34.55 g, 250 mmol) and DMAC (275 ml) washeated to 100° C. Toluene (94 ml) was added and the mixture slowlyheated to reflux. The reflux temperature was raised by distillation oftoluene and water until it reached 140° C. The mixture was then cooledto below 100° C. and 2-chloronicotinonitrile (13.86 g, 100 mmol) addedwith a toluene rinse (50 ml). The mixture was again heated to reflux andthe reflux temperature raised to 140° C. as before. Then the water trapwas filled with toluene and the reflux continued for 40 min., at whichpoint an HPLC showed no 2-chloronicotinonitrile remained but thereaction was not complete. After cooling the reaction below reflux,additional 2-chloronicotinonitrile (0.63 g, 4.5 mmol) was added andreflux continued for 90 min. The reaction was cooled to room temperatureand the solids filtered with a toluene wash. The filtrate wasconcentrated on a rotary evaporator to 41 g of syrup which was dissolvedin EtOAc (200 ml). This solution was washed with water (200 ml) and theaqueous layer back-extracted with EtOAc (50 ml). The combined organiclayers were washed with water (3×200 ml) and concentrated in vacuo to26.93 g of solid, ˜100% of theory. HPLC indicated 94.3% purity. ¹ H NMR(300 MHz, DMSO-d₆) was consistent with the desired product;

The following compounds were prepared in a manner analogous to schemesIV and/or preparations 24 through 33 described herein or by techniquesappreciated in the art:

    __________________________________________________________________________                                                      Confirmed                   Name       Structure                       m.p.                                                                              Yield                                                                            NMR                                                                              M.S.                     __________________________________________________________________________    (4-(3-oxobutyl)  phenyl)methanenitrile  Preparation 44                                    ##STR60##                      oil 33%                                                                              x  x                        (3-(3-oxobutyl)  phenyl)methanenitrile  Preparation 45                                    ##STR61##                      oil 44%                                                                              x  x                        3-(3-oxobutyl)  benzamide  Preparation 46                                                 ##STR62##                      104-6                                                                             45%                                                                              x  x                        (2-(3-oxobutyl)  phenyl)methanenitrile  Preparation 47                                    ##STR63##                      oil 43%                                                                              x  x                        (2-(3-oxobutyl)  benzamide  Preparation 48                                                ##STR64##                       113-  114                                                                        91%                                                                              x  x                        (4-(3-oxohexyl)phenyl)  methanenitrile  Preparation 49                                    ##STR65##                      oil 85%                                                                              x  x                        4-(3-oxohexyl)  benzamide  Preparation 50                                                 ##STR66##                      90-93                                                                             67%                                                                              x  x                        3-methyl-5-(4-(3-  oxobutyl)phenyl)-1H-  tetrazole  Preparation                           ##STR67##                      90-93                                                                             67%                                                                              x  x                        (4-(3-oxobutyl)phenyl)  sulfonamide  Preparation 52                                       ##STR68##                      132-4                                                                             36%                                                                              x  x                        (4-(1-methyl-3-  oxobutyl)phenyl)  methanenitrile  Preparation                            ##STR69##                      oil 44%                                                                              x  x                        3-benzyl-5-(4-(3-  oxobutyl)phenyl)-1H-  tetrazole  Preparation                           ##STR70##                      66-9                                                                              41%                                                                              x  x                        4-(1-methyl-3-  oxobutyl)benzamide  Preparation 55                                        ##STR71##                      127-9                                                                             95%                                                                              x  x                        5-(4-(3-oxobutyl)  phenyl)-1H-tetrazole  Preparation 56                                   ##STR72##                      197-9                                                                             94%                                                                              x  x                        5-(3-oxobutyl)-2-  furanoic acid  Preparation 57                                          ##STR73##                       129-  32                                                                         86%                                                                              x  x                        3-(2-fluoro-4-(3-  oxobutyl)phenyl)  propenoic acid  Preparation                          ##STR74##                      143-6                                                                             95%                                                                              x  x                        (4-(3-oxobutyl)phenyl)  ethanenitrile  Preparation 59                                     ##STR75##                      oil 100%                                                                             x  x                        (4-(3-oxobutyl)phenyl)  thioamide  Preparation 60                                         ##STR76##                      96-8                                                                              low*                                                                             x  x                        (2-fluoro-4-(3-  oxobutyl)phenyl)  methanenitrile  Preparation                            ##STR77##                      oil 78%                                                                              x  x                        2-fluoro-4-(3-  oxobutyl)benzamide  Preparation 62                                        ##STR78##                      150-3                                                                             85%                                                                              x  x                        3-methyl-5-(2-(3-  oxobutenyl)phenyl-1N-  tetrazole  Preparation                          ##STR79##                      64-5                                                                              45%                                                                              x  x                        (4-(3-oxocyclohexyl)-  phenyl)methanenitrile  Preparation                                 ##STR80##                      66-69                                                                             36%                                                                              x  x                        1-methyl-5-(2-(3-oxo-  butenyl)phenyl)-1H-  tetrazole  Preparation                        ##STR81##                       100-  102                                                                        18%                                                                              x  x                        (2,6-difluoro-(4-(3-  oxobutyl)phenyl))  sulfonamide  Preparation                         ##STR82##                      oil 41%                                                                              x  x                        N-methoxyl-4-(3-  oxobutyl)benzamide  Preparation 67                                      ##STR83##                          low                                                                              x  x                        (4-(2-methyl-3-  oxobutyl)phenylmethane  nitrile  Preparation                             ##STR84##                      oil 66%                                                                              x  x                        4-(2-methyl-3-  oxobutyl)benzamide  Preparation 69                                        ##STR85##                       112-  115                                                                        87%                                                                              x  x                        (1-methyl-2-(4-(3-  oxobutyl)phenyl)-4-  trifluoromethyl)  imidazole          Preparation 70                                                                            ##STR86##                      62-3                                                                              68%                                                                              x  x                        4-(1,2-dimethyl-3-  oxobutyl)benzamide  Preparation 71                                    ##STR87##                       100-  102                                                                        90%                                                                              x  x                        4-(3-oxocyclohexyl)  benzamide  Preparation 72                                            ##STR88##                       188-  42%                                                                        x  x                           5-(3-oxobutyl)-2-  thiophene sulfonamide  Preparation 73                                  ##STR89##                      96-98                                                                             66%                                                                              x  x                        (3-(3-oxobutyl)phenyl)  sulfonamide  Preparation 74                                       ##STR90##                      87-90                                                                             35%                                                                              x  x                        2-methyl-5-(3-(3-  oxobutyl)phenoxy)  phenyl)tetrazole  Preparation                       ##STR91##                      98  65%                                                                              x  x                        4-(3-oxocyclopentyl)  benzamide  Preparation 76                                           ##STR92##                      203-4                                                                             43%                                                                              x  x                        4-(1,1-dimethyl-3-  oxobutyl)benzamide  Preparation 77                                    ##STR93##                      106-8                                                                             61%                                                                              x  x                        (4-(3-oxocycloheptyl)  phenyl)methanenitrile  Preparation                                 ##STR94##                      oil 54%                                                                              x  x                        (4-(3-oxohexyl)phenyl)  methanenitrile  Preparation 79                                    ##STR95##                      oil 77%                                                                              x  x                        4-(3-oxobutyl)-  phthalhydrazide  Preparation 80                                          ##STR96##                      161-4                                                                             13%                                                                              x  x                        4-(3-oxohexyl)  benzamide  Preparation 81                                                 ##STR97##                       158-  61                                                                         82%                                                                              x  x                        (4-(2,2-dimethyl-3-  oxobutyl)phenyl)  methanenitrile  Preparation                        ##STR98##                      oil 72%                                                                              x  x                        4-(2,2-dimethyl-3-  oxobutyl)benzamide  Preparation 83                                    ##STR99##                       127-  131                                                                        62%                                                                              x  x                        5-(2-methyl-3-  oxobutyl)-2-thiophene  sulfonamide  Preparation                           ##STR100##                     oil low                                                                              x  x                        4-((2-oxocycloheptyl)  methyl)benzamide  Preparation 85                                   ##STR101##                     132-4                                                                             88%                                                                              x  x                        (4-((2-oxocyclopentyl)  methyl)phenyl)  methanenitrile  Preparation                       ##STR102##                     oil 62%                                                                              x  x                        4-((2-oxocyclopentyl)  methyl)benzamide  Preparation 87                                   ##STR103##                      138-  142                                                                        81%                                                                              x  x                        (4-(4-(3-oxobutyl)  phenoxy)methylphenyl)  methanenitrile  Preparation                    ##STR104##                     94-7                                                                              84%                                                                              x  x                        4-(4-(3-oxobutyl)  phenoxy)methyl  benzamide  Preparation                                 ##STR105##                      215-  17                                                                         95%                                                                              x  x                        (2-fluoro-4-(2-methyl-  3-oxobutyl)phenyl)  methanenitrile  Preparation       90                                                                                        ##STR106##                     oil 42%                                                                              x  x                        2-fluoro-4-(2-methyl-  3-oxobutyl)benzamide  Preparation                                  ##STR107##                      112-  15                                                                         93%                                                                              x  x                        5-(2-fluoro-4-(2-  methyl-3-oxobutyl)  phenyl)-1H-tetrazole  Preparation      92                                                                                        ##STR108##                     175-8                                                                             32%                                                                              x  x                        5-(3-oxobutyl)-2-  (morpholinosulfonyl)-  thiophene  Preparation                          ##STR109##                     80-83                                                                             69%                                                                              x  x                        5-(2-methyl-3-  oxobutyl)-2-  (morpholinosulfonyl)-  thiophene                Preparation 94                                                                            ##STR110##                     oil 15%                                                                              x  x                        (4-(2-(4-(3-  oxobutyl)phenoxy)  ethyl)phenyl)  methanenitrile                Preparation 95                                                                            ##STR111##                     oil 41%                                                                              x                           (4-(4-(3-oxobutyl)  phenyl)phenyl  methanenitrile  Preparation                            ##STR112##                     133-5                                                                             62%                                                                              x  x                        (2-methyl-4-(3-  oxobutyl)phenyl)  methanenitrile  Preparation                            ##STR113##                     oil 55%                                                                              x  x                        4-(4-(3-oxobutyl)  phenyl)benzamide  Preparation 98                                       ##STR114##                      229-  31                                                                         94%                                                                              x  x                        (3-methyl-4-(3-  oxobutyl)phenyl)  methanenitrile  Preparation                            ##STR115##                     34-6                                                                              75%                                                                              x  x                        2-methyl-4-(3-  oxobutyl)benzamide  Preparation 100                                       ##STR116##                      147-  50                                                                         39%                                                                              x  x                        3-methyl-4-(3-  oxobutyl)benzamide  Preparation 101                                       ##STR117##                     103-5                                                                             46%                                                                              x  x                        4-(2-(4-(3-oxobutyl)  phenoxy)ethyl)  benzamide  Preparation                              ##STR118##                      semi-  solid                                                                     17%                                                                              x  x                        4-(4-oxopentyl)  phenyl)methanenitrile  Preparation 103                                   ##STR119##                     oil quant                                                                            x  x                        4-(4-oxopentyl)  benzamide  Preparation 104                                               ##STR120##                      111-  13                                                                         87%                                                                              x  x                        (3-methyl-4-(2-methyl-  3-oxobutyl)phenyl)  methanenitrile  Preparation       105                                                                                       ##STR121##                     oil 64%                                                                              x  x                        (3-methyl-4-(2-methyl-  3-oxobutyl)benzamide  Preparation                                 ##STR122##                     105-7                                                                             71%                                                                              x  x                        (4-(2,5-dimethyl-4-(3-  oxobutyl)phenoxy)  phenyl)methanenitrile              Preparation 107                                                                           ##STR123##                     57-9                                                                              low                                                                              x  x                        4-(2-ethyl-3-  oxobutyl)benzoic acid  Prepararion 108                                     ##STR124##                     126-9                                                                             24%                                                                              x  x                        4-(2,5-dimethyl-(3-  oxobutyl)phenoxy)  benzamide  Preparation                            ##STR125##                     191-3                                                                             76%                                                                              x  x                        (4-2,6-dimethyl-(3-  oxobutyl)phenoxy)  phenyl)methanenitrile                 Preparation 110                                                                           ##STR126##                      yellow  oil                                                                      72%                                                                              x  x                        4-(2,6-dimethyl-(3-  oxobutyl)phenoxy)  benzamide  Preparation                            ##STR127##                      238-  41                                                                         63%                                                                              x  x                        __________________________________________________________________________

Example 1 is a combinatorial/parallel method for preparing compounds ofthe present invention in matrix fashion.

EXAMPLE 1

A 5×8 grid of 4 mL screw cap vials was arranged. To each of the eightrows of vials in the grid was added 33 μmol of ketone (from preparations24-37, 44-111, or commercially available), one ketone per row, as astock solution in methanol (0.5M, 65 μl). If solubility was a problem,acetonitrile/methanol or DMF was used. To each column of vials in thegrid was added 50 μmol of amine hydrochloride, one amine hydrochloride(or amine) (from preparations 1 through 16, or commercially available)per column, as a stock solution in methanol (0.5M, 100 μl). To each vialwas then added resin VIII (18-20 mg), 1.01 meq/g, 70-90μeq base). Teflonlined caps were then placed on each vial. The slurries were then shakenfor 24 hours, at which time each vial was treated with approximately 30mg (2.5 mmol BH₄ -/g resin, 75 μmol) of Amberlite IRA400 borohydrideresin (Aldrich Chemical). The caps were replaced, and the vials wereshaken for an additional 24 hours, then 150 μl methylene chloride and 40mg (1 mmol/g resin, 0.4 mmol) polystyrene-linked benzaldehyde resin(Frechet, J. M.; Schuerch, C. J. Am. Chem. Soc. 1971, 21, 492.) in orderto scavenge excess primary amine starting material were added to thevial, and the slurry was shaken for 1 day. Each vial was then filteredthrough a cotton plug. The residual resin was rinsed with three smallportions of methanol (approximately 200 μl). The resulting solutionswere then treated with 20 μl of conc. HCl (120 μmol) to ensure formationof the HCl salt of the product amine, then each vial was diluted to avolume of approximately 4 mL, and 1 mL of each solution was transferredto a tared 4 mL screw cap vial. This solution was allowed to evaporatein a fume hood under an air stream until dry, then placed in a vacuumoven for 24 hours at room temperature. The resulting residues were thenweighed and submitted directly for testing with no further purification.The bulk of the material (75%) was similarly evaporated.

The following matrices list additional examples 2-201. These compoundswere prepared using combinatorial/parallel techniques in accordance withthe present invention. All reaction conditions were the same from plateto plate and in substantial accordance with Scheme 2 and Example 1. Thescaffold for each plate was the same and is depicted at the top cornerof the 5×8 matrix. The variable functional groups are illustrated in therows and columns. The ketones and the amines depicted on each plate wereprepared in accordance with the schemes and preparations describedherein or by techniques known in the art.

       -      ##STR128##       R" =                       R'      =     ##STR129##      ##STR130##      ##STR131##      ##STR132##      ##STR133##      ##STR134##      ##STR135##      ##STR136##      ##STR137##      Example 2  Example 3  Example 4  Example 5  Example 6  Example 7     Example 8  Example 9      ##STR138##      Example 10 Example 11 Example 12 Example 13 Example 14 Example 15     Example 16 Example 17      ##STR139##      Example 18 Example 19 Example 20 Example 21 Example 22 Example 23     Example 24 Example 25      ##STR140##      Example 26 Example 27 Example 28 Example 29 Example 30 Example 31     Example 32 Example 33      ##STR141##      Example 34 Example 35 Example 36 Example 37 Example 38 Example 39     Example 40 Example 41       R" =                       R'      =     ##STR142##      ##STR143##      ##STR144##      ##STR145##      ##STR146##      ##STR147##      ##STR148##      ##STR149##      ##STR150##      Example 42 Example 43 Example 44 Example 45 Example 46 Example 47     Example 48 Example 49      ##STR151##      Example 50 Example 51 Example 52 Example 53 Example 54 Example 55     Example 56 Example 57      ##STR152##      Example 58 Example 59 Example 60 Example 61 Example 62 Example 63     Example 64 Example 65      ##STR153##      Example 66 Example 67 Example 68 Example 69 Example 70 Example 71     Example 72 Example 73      ##STR154##      Example 74 Example 75 Example 76 Example 77 Example 78 Example 79     Example 80 Example 81       R" =                       R'      =     ##STR155##      ##STR156##      ##STR157##      ##STR158##      ##STR159##      ##STR160##      ##STR161##      ##STR162##      ##STR163##      Example 82 Example 83 Example 84 Example 85 Example 86 Example 87     Example 88 Example 89      ##STR164##      Example 90 Example 91 Example 92 Example 93 Example 94 Example 95     Example 96 Example 97      ##STR165##      Example 98 Example 99  Example 100  Example 101  Example 102  Example     103  Example 104      Example 105      ##STR166##       Example 106  Example 107  Example 108  Example 109  Example 110     Example 111  Example 112      Example 113      ##STR167##       Example 114  Example 115  Example 116  Example 117  Example 118     Example 119  Example 120      Example 121       R" =                       R'      =     ##STR168##      ##STR169##      ##STR170##      ##STR171##      ##STR172##      ##STR173##      ##STR174##      ##STR175##      ##STR176##       Example 122  Example 123  Example 124  Example 125  Example 126     Example 127  Example 128      Example 129      ##STR177##       Example 130  Example 131  Example 132  Example 132  Example 133     Example 134  Example 135  Example 136      Example 137      ##STR178##       Example 138  Example 139  Example 140  Example 141  Example 142     Example 143  Example 144      Example 145      ##STR179##       Example 146  Example 147  Example 148  Example 149  Example 150     Example 151  Example 152      Example 153      ##STR180##       Example 154  Example 155  Example 156  Example 157  Example 158     Example 159  Example 160      Example 161       R" =                       R'      =     ##STR181##      ##STR182##      ##STR183##      ##STR184##      ##STR185##      ##STR186##      ##STR187##      ##STR188##      ##STR189##       Example 162  Example 163  Example 164  Example 165  Example 166     Example 167  Example 168      Example 169      ##STR190##       Example 170  Example 171  Example 172  Example 173  Example 174     Example 175  Example 176      Example 177      ##STR191##       Example 178  Example 179  Example 180  Example 181  Example 182     Example 183  Example 184      Example 185      ##STR192##       Example 186  Example 187  Example 188  Example 189  Example 190     Example 191  Example 192      Example 193      ##STR193##       Example 194  Example 195  Example 196  Example 197  Example 198     Example 199  Example 200      Example 201

EXAMPLE 2024-(3-[N-(2-[4-(5-carbamoyl-2-pyridyloxy)phenyl]-1,1-dimethylethyl)amino]-2-hydroxypropoxy)-2-indolecarboxamide##STR194##

4-(oxiranylmethoxy)-1H-indole-2-carboxamide, (2:1 with dioxane) (0.304g, 0.36 mmol, 1 eq) and the product of Preparation 40 (0.312 g, 1.09mmol, 3 eq) were suspended in absolute ethanol (15 mL). The suspensionwas heated to 50° C. at which time all of the reagents went intosolution and heating was continued for 12 hours. Upon completion of thereaction, the mixture was cooled to room temperature and crystals slowlyformed. The white solid was filtered and dried under reduced pressure toprovide 0.190 g (100% yield) of product.

Anal calcd for C₂₈ H₃₁ N₅ O₅ ; C, 64.97; H, 6.04; N, 13.53. Found; C,64.79; H, 6.08; N, 13.27.

MS: m/z (%)=517.9 (100%), 290.1 (73%), 227.0 (38%).

EXAMPLE 203(S)-4-(3-[N-(2-[4-(4-carbamoylphenoxy)phenyl]-1,1-dimethylethyl)amino]-2-hydroxypropoxy)indole##STR195##

A stirred mixture of (S)-(+)-(oxiranylmethoxy)-1H-indole (7.00 g, 37.0mmol) and 4-(4-(2-amino-2-methylpropyl)phenoxy)benzamide (21.0 g, 73.8mmol) in methanol (260 mL) was heated to 45° C. for 22 hours. Themixture was then heated an additional 4 hours at 60° C. The reactionmixture was concentrated in vacuo to an oily residue. The residue waspartitioned with ethyl acetate (200 mL), water (35 mL), and 1N HCl (33mL). The organic solution was washed two times with a solution of 1N HCl(2 mL) in water (33 mL). The ethyl acetate solution was dried with Na₂SO₄, filtered, and the filtrate was concentrated in vacuo to a foamypale yellow residue. The crude product was purified by flashchromatography with 400 g 230-400 mesh silica gel and ethylacetate:ethanol (5:1 to 4:1 gradient). Concentration of the appropriatefractions afforded 14.8 g (84.5%) of the desired product as a whitefoamy solid. ¹ H NMR (DMSO-d₆) was consistent with the desired product.

EXAMPLE 204(S)-4-(3-[N-(2-[4-(4-carbamoylphenoxy)phenyl]-1,1-dimethylethyl)amino]-2-hydroxypropoxy)indolehydrochloride salt ##STR196##

A stirred solution of the product of Example 203 (11.48 g, 24.24 mmol)in ethyl acetate (150 mL) was treated by slow addition with of a 1MHCl/ethyl acetate (24 mL, 24 mmol) solution at ambient temperature. Anadditional EtOAc (50 mL) was added to the resulting white precipitate,and the slurry was stirred approximately 1 hour at ambient temperature.The product slurry was pressure filtered through a stainless steelfilter under nitrogen. The collected product was kept under a steadynitrogen purge for approx. 2 hrs. The filter was then placed in a vacuumoven overnight at 60° C. The product was dried to constant weight in adrying oven at 75° C. to afford 10.38 g (84.1%) as a white solid.

¹ H NMR (DMSO-d₆): δ1.22 (s, 6H), δ2.8-3.5 (m, 5H), δ4.05-4.35 (m, 3H),δ6.45-6.55 (m, 2H), δ6.95-7.40 (m, 6H), δ7.15-7.40 (m, 4H), δ7.85-8.05(m, 3H), δ11.10 (br. s, 1H).

EA: Calculated for C₂₈ H₃₂ ClN₃ O₄ : C 65.94, H 6.32, N 8.24. Found: C65.72, H 6.25, N 7.97.

EXAMPLE 205(S)-4-(3-[N-(2-[4-(5-carbamoyl-2-pyridyloxy)phenyl]-1,1-dimethylethyl)amino]-2-hydroxypropoxy)indolehydrochloride salt ##STR197##

A mixture of 4-(2-amino-2-methylpropyl)phenoxy)-5-carboxamidepyridine(21.11 g, 74.00 mmol), (S)-(+)-4-(oxiranylmethoxy)-1H-indole (7.00 g,37.00 mmol), HOAc (90.4 mg, 1.48 mmol), and water (12 mL) in MeOH (260mL) was stirred at 60° C. for 19.25 hours. The mixture was cooled andconcentrated in vacuo to an oil. The residue was dissolved in EtOAc (185ml) and water (75 mL) and the resulting layers were separated. Theorganic layer was extracted with solutions of 1N HCl (34 mL), 1NHCl/MeOH (30 mL/5 mL), 1N HCl/water/MeOH (15 mL/20 mL/10 mL), and 1N HCl(10 mL). The combined acidic aqueous extracts (containing excessstarting amine and product) were washed with EtOAc (40 mL). The organiclayers were combined and discarded. The pH of the aqueous layer was madeslightly basic (pH 7.0-7.5) with the addition of 5N NaOH (10 mL) and 1NHCl (1 mL). The aqueous layer was then extracted with EtOAc (100 mL,2×50 mL). The pH of the aqueous layer was raised slightly with theaddition of 5N NaOH (0.25 mL). The aqueous layer was diluted with water(5 mL) and MeOH (5 mL) and then was extracted with EtOAc (2×50 mL). ThepH of the aqueous layer was raised with 5N NaOH (1 mL) and the layer wasextracted with more EtOAc (2×50 mL). The pH of the aqueous layer wasagain raised with the addition of 5N NaOH (1 mL) and the layer was againextracted with EtOAc (2 ×50 mL). The combined organic extracts of thebasic aqueous layer were concentrated in vacuo to approximately 300 mL.The organic layer was washed with water (50 mL) and then wasconcentrated in vacuo to 16.64 g of an oil. Purification of 16.31 g ofthe oil by flash chromatography over 230-400 mesh silica gel using25:4:0.1 chloroform/methanol/˜28% ammonia as an eluent yielded 13.35 g(76.02%) of the free base as product. ¹ H NMR (DMSO-d₆) was consistentwith the desired product.

A stirred solution of the free base (11.86 g, 25.00 mmol) in EtOAc (280mL) and isopropanol (20 mL) was made acidic with the dropwise additionof 34 mL (approx. 25 mmol HCl) of an approximately 0.725M HCl(g) inEtOAc solution. The resulting slurry was stirred for 2 hours at ambienttemperature. The mixture was filtered (nitrogen pressure). The filtercake was washed twice with EtOAc (2×20 mL) and dried in vacuo at 50° C.to yield 12.48 g (97.65%) of a white powder. ¹ H NMR was consistent withthe desired product and showed small amounts of EtOAc, IPA, and water):

¹ H NMR (500 MHz, DMSO-d₆): δ11.14 (s, 1H), 9.1 (br s, 1H), 8.7 (br s,1H), 8.64 (d, 1H), 8.29-8.27 (m, 1H), 8.08 (s, 1H), 7.50 (s, 1H),7.30-7.29 (d, 2H), 7.24-7.23 (m, 1H), 7.14-6.99 (m, 5H), 6.54-6.49 (m,2H), 5.93 (br s, 1H), 4.33 (m, 1H), 4.19-4.11 (m, 2H), 3.35 (m, 1H),3.14 (m, 1H), 3.04 (m, 2H), 1.27 (s, 6H); MS (FD+) m/z 949 (31%), 475(100%).

EXAMPLE 206(S)-4-(3-[N-(2-[4-(4-carbamoylphenoxy)phenyl]-1,1-dimethylethyl)amino]-2-hydroxypropoxy)benzotriazole##STR198##

The diamino product from preparation 20 (0.304 g, 0.65 mmol) wasdissolved in glacial acetic acid (10 mL) and treated with a solution ofsodium nitrite (0.047 g, 0.68 mmol) in water (5 mL) all at once. Thereaction was stirred for 5 min and then evaporated to dryness. Theresulting residue was purified using column chromatography eluting with20% MeOH/CHCl₃ to provide 0.27 g (87%) as a solid.

MS: m/z (%)=475.9 (100%), 249.0 (5%), 950.7 (5%)

¹ H NMR (300 MHz, d-MeOH): δ1.35 (6H, s); 3.03 (2H, s); 3.40 (2H, m);4.35 (3H, m); 6.95 (1H, d); 7.02 (4H, m); 7.31 (2H, d); 7.38 (2H, d);7.87 (3H, d).

EXAMPLE 207(S)-4-(3-[N-(3-[4-carbamoylphenyl]-1,1-dimethylpropyl)amino]-2-hydroxypropoxy)benzotriazole##STR199##

The above titled compound, 0.086 g (63%) was obtained by a proceduredescribed in Example 206 starting from 0.113 g of the appropriatediamine.

MS: m/z (%): 398.3 (100%); 796.1 (20%)

¹ H NMR (300 MHz, d-MeOH): d 1.3 (6H, s); 1.85 (2H, m); 2.65 (2H, m);3.02 (2H, m); 4.2 (3H, m); 6.72 (1H, d); 7.20 (1H, d); 7.25 (2H, d);7.35 (1H, d); 7.75 (2H, d).

EXAMPLE 208(S)-4-(3-[N-(3-[4-(4-carbamoylphenoxy)phenyl]-1,1-dimethylpropyl)amino]-2-hydroxypropoxy)benzotriazole##STR200##

The above titled compound, 0.163 g (69%) was obtained by a proceduredescribed in Example 206 starting from 0.231 g of the appropriatediamine.

MS: m/z (%): 490.0 (100%, m⁺ +1)

¹ H NMR (300 MHz, d-MeOH): d 1.42 (6H, s); 1.98 (2H, m); 2.70 (2H, m);3.20 (2H, m); 4.30 (3H, s); 6.80 (1H, m); 6.98 (4H, m); 7.25 (2H, d);7.35 (2H, d); 7.85 (2H, d).

EXAMPLE 209(S)-4-(3-[N-(2-[4-(5-carbamoyl-2-pyridyloxy)phenyl]-1,1-dimethylethyl)amino]-2-hydroxypropoxy)benzotriazole##STR201##

The above titled compound, 0.156 g (65%) was obtained by a proceduredescribed in Example 206 starting from 0.235 g of the appropriatediamine.

MS: m/z (%): 477.0 (100%, m⁺ +1)

¹ H NMR (300 MHz, d-MeOH): d 1.21 (6H, s); 2.90 (2H, s); 3.15 (2H, m);4.25 (3H, m); 6.79 (1H, d); 7.0 (3H, m); 7.3 (4H, m); 8.25 (1H, d); 8.6(1H, s).

EXAMPLE 210(S)-4-(3-[N-(2-[4-([4-methoxycarbonylphenyl]methoxy)phenyl]-1,1-dimethylethyl)amino]-2-hydroxypropoxy)benzotriazole##STR202##

The above titled compound, 0.093 g (65%) was obtained by a proceduredescribed in Example 206 starting from 0.109 g of the appropriatediamine.

MS: m/z (%): 505.1 (100%, m⁺ +1)

¹ H NMR (300 MHz, d-MeOH): 1.3 (6H, s); 2.95 (2H, s); 3.25 (2H, m); 3.95(3H, s); 4.30 (3H, m); 5.16 (2H, s); 6.85 (1H, d); 6.90 (2H, d); 7.20(2H, d); 7.40 (2H, m); 7.60 (2H, d); 8.15 (2H, d).

EXAMPLE 211(S)-4-(3-[N-(3-[4-(N-benzylcarbamoyl)phenyl]-1,1-dimethylpropyl)amino]-2-hydroxypropoxy)benzotriazole##STR203##

The above titled compound, 0.160 g (63%) was obtained by a proceduredescribed in Example 206 starting from 0.211 g of the appropriatediamine.

MS: m/z (%): 488 (100%, m⁺ +1)

¹ H NMR (300 MHz, d-MeOH): 1.45 (6H, s); 2.0 (2H, m); 2.8 (2H, m); 3.25(2H, m); 4.35 (3H, s); 4.6 (2H, s); 6.85 (1H, m); 7.25 (1H, m); 7.35(8H, m); 7.80 (2H, d).

EXAMPLE 212(S)-4-(3-[N-(2-[4-(4-carbamoylphenoxy)phenyl]-1,1-dimethylethyl)amino]-2-hydroxypropoxy)-2-oxo-2,3-1H-benzoimidazolehydrochloride salt ##STR204##

Crude 4-(4-(2-(N-((2S)-3-(2,3-diaminophenoxy)-2-hydroxypropyl)amino)-2-methylpropyl)phenoxy)benzamide (1.49 g, 3.2 mmol) fromPreparation 20 was dissolved in 1N HCl (100 mL). Toluene (100 mL) wasadded and the biphasic mixture treated with triphosgene (4.7 g, 16 mmol)and stirred vigorously for 18 h. A gum precipitated on the sides of thereaction vessel during the course of the reaction. The liquid wasdecanted off and the gum dissolved in MeOH. The solution was absorbed onsilica and chromatographed on 200 g of silica eluting withEtOAc/water/n-propanol (80 vol/15 vol/5 vol, shake and use top layer) toremove the starting material. The column was then eluted with CHCl₃/MeOH/NH₄ OH (25 vol/5 vol/1 vol) to obtain the product. Afterconcentrating and azeotroping with EtOH there was obtained 715 mg (46%)of a white foam. MS. ¹ H NMR (DMSO-d₆) consistent with desired product.

The free base (528 mg, 1.08 mmol) prepared above was dissolved in EtOHand treated with 4N HCl in dioxane (0.75 mL, 3.0 mmol). The solution wasconcentrated in vacuo to provide 595 mg of a white foam as thehydrochloride salt. MS. ¹ H NMR (DMSO-d₆) consistent with desiredproduct.

As previously noted, the compounds of the present invention are potent,selective β₃ adrenergic receptor agonists. This pharmacological activitywas determined in the functional agonist β₃ assay.

Functional Agonists β₃ Assay

Cell Lines

The hβ₂ DNA was expressed from a plasmid 57537 obtained from AmericanType Culture Collection. hβ₁ and hβ₃ adrenergic receptors were clonedfrom human genomic libraries using the polymerase chain reaction methodwith degenerate probes. Full length receptors were cloned, expressed andsequenced to verify identity according to published sequences (hβ₁ : T.Frielle et. al. (1993) Molecular Pharmacology 44: 264-270). Thesereceptors were then expressed in the DXB-11 variant of CHO cells using avector restoring tetrahydrofolate reductase and hygromycin resistance.Rat β₃ receptor expressing CHO cell line is known in the art. Mol.Pharm., Vol 40, pp. 895-99 (1991). CHO cells were grown in 10% dialyzedFBS./high glucose DMEM/0.1% proline.

cAMP Assay

Cell membranes were harvested from the above cell line using hypotonic25 mM Hepes (pH 7.4), 1 mM EDTA, 20 μg/mL leupeptin, 1 mM PMSF bufferwith scraping followed by differential centrifugation. Membranes wereincubated in 25 mM Tris (pH 7.6), 0.2% BSA, 2.6 mM Mg, 0.8 mM ATP, 0.1mM GTP, 5 mM creatine phosphate, creatine kinase 50 U/mL, 0.2 mM IBMX at32° C. Agonists were added and incubation continued for 15 m. cAMPproduced was assayed using a fluorescent tracer-immuno assay method.

Intact cell assays were performed using suspended cells removed fromculture flasks by trypsin treatment. Cells were preincubated with 0.5 mMIBMX at 37° C. Agonists were added and incubation continued for 15 m.Incubation was stopped by heating suspension in boiling water. cAMP orcGMP in these and the soleus incubations were assayed by RIA (Amersham).

The compounds of the invention are agonists of the β₃ receptor.Isoproterenol is accepted in the art as a non-selective β₃ agonist andis widely used as a comparator in evaluating the activity of compounds.See Trends in Pharm. Sci. 15: 3 (1994). In the Functional Agonist β₃assay, the compounds demonstrated at least 30%, preferably 50% and mostpreferably over 85% of isoproterenol's response at a single dose of50μmol. Dose response titrations on the agonists described reveal EC₅₀values of <10 μM, preferably <1mmol. In the functional assay, dosetitration furnishes an EC₅₀ for isoproterenol of 1.1±0.5 μM.

When screened against the β₁ and β₂ receptors in the functional assay,dose titration experiments indicate that greatly reduced or no receptorstimulation is observed with the compounds of the invention. This isdefined by measuring the intrinsic activity (maximal response achieved)as compared to isoproterenol. The claimed compounds of Formula I areselective β₃ receptor agonists and have an intrinsic activity of <3% ofisoproterenol's response.

Thus, the compounds of the invention are selective β₃ adrenergicreceptor agonists.

As agonists of β₃, the compounds are useful in treating conditions in amammal in which the β₃ receptor has been demonstrated to play a role.The prefered mammal of treatment is a human. The relationship betweenmodulating the β₃ receptor and treatment of diseases, such Type IIdiabetes and obesity, is well established in the art. Other conditionsrecognized in the art include: gastrointestinal disorders such asgastrointestinal motility, asthma, and depression. Thus, the presentcompounds are useful in the treatment of inflammatory bowel disease(Crohn's disease or ulcerative colitis), irritable bowel syndrome,non-specific diarrhoea dumping syndrome, asthma, and depression.

In treating non-human mammals, the compounds of the present inventionare useful for increasing weight gain and/or improving the feedutilization efficiency and/or increasing lean body mass and/ordecreasing birth mortality rate and increasing post/natal survival rate.

The compounds of Formulas I and II are preferably formulated prior toadministration. Therefore, yet another embodiment of the presentinvention is a pharmaceutical formulation comprising a compound ofFormula I or II and one or more pharmaceutically acceptable carriers,diluents or excipients.

The present pharmaceutical formulations are prepared by known proceduresusing well-known and readily available ingredients. In making thecompositions of the present invention, the active ingredient willusually be mixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier which may be in the form of a capsule, sachet, paper orother container. When the carrier serves as a diluent, it may be asolid, semisolid or liquid material which acts as a vehicle, excipientor medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solidor in a liquid medium), soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.1 to about 500 mg, preferably about 5 toabout 200 mg, of the active ingredient. However, it will be understoodthat the therapeutic dosage administered will be determined by thephysician in the light of the relevant circumstances including thecondition to be treated, the choice of compound to be administered andthe chosen route of administration, and therefore, the above dosageranges are not intended to limit the scope of the invention in any way.The compounds can be administered by a variety of routes including theoral, rectal, transdermal, subcutaneous, topical, intravenous,intramuscular or intranasal routes. For all indications, a typical dailydose will contain from about 0.05 mg/kg to about 20 mg/kg of the activecompound of this invention. Preferred daily doses will be about 0.1 toabout 10 mg/kg, ideally about 0.1 to about 5 mg/kg. However, for topicaladministration a typical dosage is about 1 to about 500 μg compound percm² of an affected tissue. Preferably, the applied amount of compoundwill range from about 30 to about 300 μg/cm², more preferably, fromabout 50 to about 200 μg/cm², and, most preferably, from about 60 toabout 100 μg/cm².

The following formulation examples are illustrative only and are notintended to limit the scope of the invention in any way.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                            Quantity                                                                       (mg/capsule)                                             ______________________________________                                        (S)-4-(3-[N-(2-[4-(4- 25                                                        carbamoylphenoxy)phenyl]-1,1-                                                 dimethylethyl)amino]-2-                                                       hydroxypropoxy)indole hydrochloride                                           salt                                                                          starch, dried 425                                                             magnesium stearate 10                                                       Total                 460 mg                                                  ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

The principles, preferred embodiments and modes of operation of thepresent invention have been described in the foregoing specification.The invention which is intended to be protected herein, however, is notto be construed as limited to the particular forms disclosed, since theyare to be regarded as illustrative rather than restrictive. Variationsand changes may be made by those skilled in the art without departingfrom the spirit of the invention.

We claim:
 1. A compound of the Formula ##STR205## wherein: X₁ is --OCH₂--, --SCH₂ --, or a bond;R₁ is a fused heterocycle of the formula:##STR206## R₂ and R₃ are independently H, C₁ -C₄ alkyl, or aryl; R₄ isan optionally substituted heterocycle or a moiety selected from thegroup consisting of: ##STR207## X₂ is a bond, or a 1 to 5 carbonstraight or branched alkaline; R₅ is H, or C₁ -C₄ alkyl; R₆ is H, or C₁-C₄ alkyl; or R₅ and R₆ combine with the carbon to which each isattached to form a C₃ -C₆ cycloalkyl; or R₆ combines with to X₂ and thecarbon to which X₂ is attached to form a C₃ -C₈ cycloalkyl; or R₆combines with X₂, the carbon to which X₂ is attached, and R₄ to form:##STR208## provided that R₅ is H; R₇ is H, halo, hydroxy, C₁ -C₄ alkyl,C₁ -C₄ haloalkyl, aryl, CN, COOR₂, CONHR₂, NHCOR₂, OR₂, NHR₂, SR₂, SO₂R₂, SO₂ NHR₂, or SOR₂ ; R₈ is independently H, halo or C₁ -C₄ alkyl; R₉is halo, CN, OR₁₀, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, CO₂ R₂, CONR₁₁ R₁₂,CONH(C₁ -C₄ alkyl), SR₂, CSNR₂, CSNR₁₁ R₁₂, SO₂ R₂, SO₂ NR₁₁ R₁₂, SOR₂,NR₁₁ R₁₂, optionally substituted aryl, optionally substitutedheterocycle, or C₂ -C₄ alkenyl substituted with CN, CO₂ R₂ or CONR₁₁ R₁₂; R₁₀ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, (CH₂)_(n) C₃ -C₈ cycloalkyl,(CH₂)_(n) aryl, (CH₂)_(n) heterocycle, (CH₂)_(n) C₃ -C₈ optionallysubstituted cycloalkyl, (CH₂)_(n) optionally substituted aryl, (CH₂)_(n)optionally substituted heterocycle; R₁₁ and R₁₂ are independently H, C₁-C₄ alkyl, aryl, (CH₂)_(n) aryl, or combine with the nitrogen to whicheach is bound to form morpholinyl, piperidinyl, pyrrolidinyl, orpiperazinyl; A₁ and A₂ are independently O, S, NH, CH₂, NCH₃, or NCH₂CH₃ ; m is 0 or 1; n is 0, 1, 2, or 3; provided that when R₄ is##STR209## then R₉ is not halo, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, SR₂, SO₂R₂, or SOR₂ ; and R₁₀ is not C₁ -C₄ alkyl; when R₄ is ##STR210## then R₉is not C₁ -C₄ alkyl, aryl or aryl substituted with C₁ -C₄ alkyl; andwhen R₄ is ##STR211## then R₉ is not C₁ -C₄ alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1, wherein R₇ is H,halo, hydroxy, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, NH₂, SR₂, SO₂ R₂, or SOR₂.3. A compound of claim 2 wherein: R₁ is ##STR212##
 4. A compound ofclaim 3 wherein R₅ and R₆ are methyl; and A₁ and A₂ are NH.
 5. Acompound of claim 4 wherein R₄ is
 6. A compound of claim 5 wherein R₄ is7. A compound of claim 6 wherein R₁₀ is phenyl or pyridyl; said phenylor pyridyl being substituted with --CONR₁₁ R₁₂, --CO₂ R₂, --SO₂ R₂, or--SO₂ NR₁₁ R₁₂.
 8. A method of treating Type II Diabetes comprisingadministering to a mammal in need thereof a compound of claim
 1. 9. Amethod of treating Type II Diabetes comprising administering to a mammalin need thereof a compound of claim
 7. 10. A method of treating obesitycomprising administering to a mammal in need thereof a compound ofclaim
 1. 11. A method of treating obesity comprising administering to amammal in need thereof a compound of claim
 7. 12. A method of agonizingthe β₃ receptor comprising administering to a mammal in need thereof acompound of claim
 1. 13. A method of agonizing the β₃ receptorcomprising administering to a mammal in need thereof a compound of claim7.
 14. A pharmaceutical formulation comprising as an active ingredient acompound of claim 1, associated with one or more pharmaceuticallyacceptable carriers, excipients or diluents.
 15. A pharmaceuticalformulation comprising as an active ingredient a compound of claim 7,associated with one or more pharmaceutically acceptable carriers,excipients or diluents.
 16. A compound of the Formula I: wherein:X₁ is--OCH₂ --, --SCH₂ --, or a bond; R₁ is a fused heterocycle of theformula: ##STR213## R₂ and R₃ are independently H, C₁ -C₄ alkyl, oraryl; R₄ is an optionally substituted heterocycle or a moiety selectedfrom the group consisting of: ##STR214## X₂ is a bond, or a 1 to 5carbon straight or branched alkaline; R₅ is H, or C₁ -C₄ alkyl; R₆ is H,or C₁ -C₄ alkyl; or R₅ and R₆ combine with the carbon to which each isattached to form a C₃ -C₆ cycloalkyl; or R₆ combines with to X₂ and thecarbon to which X₂ is attached to form a C₃ -C₈ cycloalkyl; or R₆combines with X₂, the carbon to which X₂ is attached, and R₄ to form:##STR215## provided that R₅ is H; R₇ is H, halo, hydroxy, C₁ -C₄ alkyl,C₁ -C₄ haloalkyl, aryl, CN, COOR₂, CONHR₂, NHCOR₂, OR₂, NHR₂, SR₂, SO₂R₂, SO₂ NHR₂, or SOR₂ ; R₈ is independently H, halo or C₁ -C₄ alkyl; R₉is halo, CN, OR₁₀, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, CO₂ R₂, CONR₁₁ R₁₂,CONH(C₁ -C₄ alkyl), SR₂, CSNR₂, CSNR₁₁ R₁₂, SO₂ R₂, SO₂ NR₁₁ R₁₂, SOR₂,NR₁₁ R₁₂, optionally substituted aryl, optionally substitutedheterocycle, or C₂ -C₄ alkenyl substituted with CN, CO₂ R₂ or CONR₁₁ R₁₂; R₁₀ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, (CH₂)_(n) C₃ -C₈ cycloalkyl,(CH₂)_(n) aryl, (CH₂)_(n) heterocycle, (CH₂)_(n) C₃ -C₈ optionallysubstituted cycloalkyl, (CH₂)_(n) optionally substituted aryl, (CH₂)_(n)optionally substituted heterocycle; R₁₁ and R₁₂ are independently H, C₁-C₄ alkyl, aryl, (CH₂)_(n) aryl, or combine with the nitrogen to whicheach is bound to form morpholinyl, piperidinyl, pyrrolidinyl, orpiperazinyl; A₁ and A₂ are independently O, S, NH, CH₂, NCH₃, or NCH₂CH₃ ; m is 0 or 1; n is 0, 1, 2, or 3; provided that when R₁ is##STR216## and R₇ is H, C1-C4 alkyl, C1-C4 haloalkyl, halo, hydroxy,OR₂, SR₂, SO₂ R₂ or SOR₂ then R₉ is not halo, C₁ -C₄ alkyl, C_(l) -C₄haloalkyl, SR₂, SO₂ R₂, SOR₂, aryl or aryl substituted with C1-C4 alkyland R₁₀ is not C1-C4 alkyl, or a pharmaceutically acceptable saltthereof.